Methods for administering small volume oral transmucosal dosage forms using a dispensing device

ABSTRACT

Systems and methods for administration of small volume sufentanil drug dosage forms to the sublingual mucosa of a subject using a device are disclosed. The dispensing device includes a lock-out feature and a means to retard or prevent saliva and/or moisture ingress such that the drug dosage forms in the device remain dry prior to administration.

CROSS REFERENCE TO OTHER APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/980,216, filed Oct. 30, 2007, which is acontinuation-in-part of U.S. patent application Ser. No. 11/825,212,filed Jul. 3, 2007 and of U.S. patent application Ser. No. 11/650,174,filed Jan. 5, 2007 (now U.S. Pat. No. 8,202,535), each of which isincorporated by reference herein in its entirety. U.S. patentapplication Ser. No. 11/650,174 claims priority benefit of U.S.provisional application No. 60/756,937, filed Jan. 6, 2006, which isincorporated by reference herein in its entirety. U.S. patentapplication Ser. No. 11/825,212 is a continuation-in-part of U.S. patentapplication Ser. No. 11/650,230, filed Jan. 5, 2007, which claimspriority benefit of U.S. provisional application No. 60/756,937, each ofwhich is incorporated by reference herein in its entirety.

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/825,212, filed Jul. 3, 2007, which is a continuation-in-partof U.S. patent application Ser. No. 11/650,230, filed Jan. 5, 2007,which claims priority benefit of U.S. provisional application No.60/756,937, each of which is incorporated by reference herein in itsentirety.

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/650,230, filed Jan. 5, 2007, which claims priority benefitof U.S. provisional application No. 60/756,937, each of which isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The invention relates to drug dispensing devices and systems for oraltransmucosal administration of small volume drug dosage forms to asubject, wherein the drug dosage forms comprise an opioid for treatmentof pain.

BACKGROUND OF THE INVENTION

Oral dosage forms account for approximately eighty percent of all thedrug dosage forms on the market. Oral dosage forms are non-invasive,easily administered and have high patient compliance.

Orally administered therapeutic agents are rapidly transported to thestomach and small intestine for absorption across the gastrointestinal(GI) mucosal membranes into the blood. The efficiency of absorption of adrug following oral administration can be low because of metabolismwithin the GI tract and first-pass metabolism within the liver resultingin relatively lengthy onset times or erratic absorption characteristicsthat are not well suited to control acute disorders. The majority oforal dosage forms on the market are designed for GI delivery. Relativelyfew oral dosage forms are designed for delivery through the oral mucosa.

However, oral transmucosal delivery offers a number of advantages inthat it can provide a shorter onset time to maximal plasma concentration(C_(max)) than oral delivery, in particular for lipophilic drugs. Thisis because the drug rapidly passes directly and efficiently through theepithelium of the highly vascularized mucosal tissue to the plasma, thusrapidly reaching the circulation while avoiding the slower, ofteninefficient and variable GI uptake. It is therefore advantageous for adrug to be delivered through the mucus membranes of the oral cavity,(e.g., via the sublingual route), when rapid onset, consistent T_(max)and C_(max) are advantageous.

In carrying out oral transmucosal drug delivery, the drug is absorbedthrough the epithelial membranes of the oral cavity. However, frequentlythe key risk associated with oral transmucosal delivery is the enhancedpotential for swallowing the medication owing to the continuousgeneration, backward flow and swallowing of the saliva. This becomes aparticular risk when the used dosage forms are large enough to produce asignificant saliva response, which, in turn, leads to swallowing or drugand/or removal of the dosage form from the oral mucosa.

Various solid dosage forms, such as sublingual tablets, troches,lozenges, lozenges-on-a-stick, chewing gums, and buccal patches havebeen used to deliver drugs via the oral mucosal tissue. Solid dosageforms such as lozenges and tablets have been used for oral transmucosaldelivery of drugs, e.g., nitroglycerin sublingual tablets.

The relevant art does not describe a dispensing device for delivery of adrug dosage form to the oral mucosa, such as the sublingual space, wherethe device facilitates proper placement of the drug dosage form.

Reproducible and effective drug delivery technology represents an areaof active research, in particular, as it applies to controlledsubstances such as opioids. Controlled access oral transmucosal drugdispensing systems offer numerous advantages over conventional means ofdrug administration such as oral and intravenous routes, the mostimportant of which is enhanced safety, with additional advantages beingrapid and consistent onset of action, more consistent and predictableplasma concentrations and higher and more consistent bioavailabilitythan currently available dosage forms.

This is particularly relevant to the treatment of pain, morespecifically, acute, intermittent and breakthrough pain.

Therefore, a need exists for a device and system that can be used toadminister a controlled substance, such as an opioid (e.g., bypatient-controlled administration), for treatment of pain, wherein thedevice provides for safe and controlled delivery via the oral mucosa,while minimizing the potential for drug abuse and/or diversion.

The present invention addresses these needs.

BRIEF SUMMARY OF THE INVENTION

The invention provides methods, systems and kits for sublingualadministration of a bioadhesive small volume sufentanil-containing drugdosage form to a subject using a device.

The device is hand-held and comprises a cartridge containing one or moredrug dosage forms (typically from 1 to about 200) dosage forms.

Each dosage form comprises 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40mcg, 50 mcg, 60 mcg, 70 mcg, 80 mcg or 100 mcg of sufentanil and has avolume of less than 100 microliters or a mass of less than 100 mg.

In carrying out the method, the dispensing end of the device is insertedinto the mouth of the subject and a dosage form is dispensed through thedispensing end of the device such that it is placed on a sublingualmembrane (in the sublingual space) of the subject.

The dispensing end of the device has a proboscis comprising a shroud forplacing the dosage form and the shroud includes a means to prevent orretard saliva and other moisture ingress into the device, such that thedosage forms remain dry prior to placement on the sublingual membrane.

The device further comprises a lock-out feature for setting a lock-outtime wherein a dosage form cannot be dispensed from the device duringthe lock-out time. The lock-out time may be a fixed time lock-outinterval, a predetermined lock-out interval, a predetermined variablelock-out interval, a lock-out interval determined by an algorithm or avariable lock-out interval communicated to the device from a remotecomputer, docking station or other device.

The cartridge may comprise one or more shipping tablets wherein at leastone shipping tablet is dispensed prior to dispensing of a dosage form.

The cartridge may include a smart cartridge recognition systemcomprising a physical keyed feature on the cartridge, an opticallydetected feature or pattern, a bar code on the cartridge, a magnetic tagon the cartridge, an RFID tag on the cartridge, an electronic microchipon the cartridge, or a combination thereof.

The dispensing device further comprises a patient identification meanswherein the patient identification means is a radio frequencyidentification (RFID) reader configured to couple with a matching RFIDtag on a patient to be identified and the dispensing device is unlockedwhen the RFID reader on the dispensing device detects a matching RFIDtag on a patient.

The dispensing device may also comprise a means for recording dosing,use history, or both, alone or in combination with a means to view ordownload the dosing and/or use history.

Following placement of a dosage from on the sublingual membrane of thesubject, erosion of the dosage form is complete in from about 30 secondsto about 30 minutes.

In carrying out the method, a single sublingual administration of adosage form to a subject results in a bioavailability of at least 50%,an AUC with a coefficient of variation of less than 40%, a T_(max) witha coefficient of variation of less than 40%; repeated sublingualadministration of a dosage form to a subject results in abioavailability that is greater than the bioavailability following asingle sublingual administration to the subject and the T_(max)following repeated sublingual administration and the time of theprevious sublingual administration is shorter than the T_(max) followinga single sublingual administration to the subject.

When a bioadhesive small volume sufentanil-containing drug dosage formis administered to the sublingual cavity of subject using a device, anamount of drug selected from the group consisting of at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 98% and at least 99% ofthe total amount of drug in the dosage form is absorbed via thesublingual route.

Administration of a sufentanil-containing drug dosage form using a drugdispensing device may be patient controlled and may be used for treatingpain in a subject, wherein following administration of the dosage form,pain relief is evident.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic depiction of an exemplary dispensing device ofthe invention wherein the device is designed to deliver drug dosageforms to the sublingual space of a patient under treatment, wherein agraphic display, a biometric patient identification reader, a dispensingbutton, a user interface, and a housing in which a dispensing cartridgeis located are illustrated.

FIG. 1B is a schematic depiction of an exemplary dispensing device ofthe invention wherein the device is designed to deliver drug dosageforms to the sublingual space of a patient under treatment, wherein adocking connector is illustrated.

FIG. 1C is a schematic depiction of an exemplary dispensing device ofthe invention wherein the device is designed to deliver drug dosageforms to the sublingual space of a patient under treatment, wherein adispensing shuttle mechanism and a dispensing end are illustrated.

FIG. 1D is a schematic depiction of an exemplary dispensing device ofthe invention wherein the device is designed to deliver drug dosageforms to the sublingual space of a patient under treatment, wherein acartridge assembly; batteries; processor and pc board; antenna; andantagonist reservoir are shown.

FIG. 2 is a schematic depiction of a cartridge assembly for use in adispensing device for delivering drug dosage forms.

FIGS. 3A-E provide a schematic depiction of an exemplary dispensingdevice wherein the device is designed to deliver drug dosage forms tooral mucosa of a patient under treatment. FIGS. 3A-E illustrate theprogression of intact drug dispensing device 5011 (FIG. 3A); thereusable head 5013 and disposable body 5015 of a drug dispensing device(FIG. 3B); a reusable head 5013, disposable body 5015 and cartridge5017, a dispense button 5023, and a proboscis 5031 of a drug dispensingdevice (FIG. 3C); various aspects of a drug dispensing device 5011including a reusable head 5013, disposable body 5015 and cartridge 5017,a proboscis 5031, and a latch 5019 to unlock the device, a hub lock5021, a distal seal 5033, 5035, and a power train coupling 5025 (FIG.3D); and a reassembled intact drug dispensing device 5011 (FIG. 3E).

FIG. 4 is a schematic depiction of an exemplary dispensing deviceshowing features designed to block or retard saliva and moistureingress. The preferred embodiment includes a dispensing tip defining anexit port 5036, having a shroud 5029, and having one or more of: awiping seal/valve 5033, 5035, an absorbent pad 5039, a pushrod 5051, adrying chamber/moisture communication channel 5043, desiccant 5045 inthe channel 5043, a cartridge 5017 containing dosage forms 5067 anddesiccant 5047 in the cartridge 5017.

FIGS. 5A and 5B are schematic depictions of an exemplary geometry for adispensing tip.

FIGS. 6A-D are a schematic depiction of an exemplary proboscis 5031 of adispensing device wherein the proboscis 5031 has an S-shape 5053 andcomprises a shroud 5029 and a valve.

The shroud shields the valve from moisture and saliva ingress from thetongue and other mucosa and provides an area for the dosage form to exitthe device without “sticking” to the wetted distal valve or shroud area.The shroud also comprises a cut-out/relief 5055 in order to mitigate thedragging of dosage forms when the device is removed from the oral space.The valve functions with the shroud to control saliva and moistureingress, as well as aid in delivery of the dosage form.

FIGS. 7A and 7B are schematic depictions of dispensing devices of theinvention showing a drug dosage form being pushed through a seal by apushrod, wherein the geometry of the seal is tailored to the shape ofthe dosage form and pushrod.

FIG. 8 is a schematic depiction of the geometry of an exemplary pushrod,drug dosage form, and septum-type seal. The exemplary slit type septumseal is designed to maintain a uniform seal around a drug dosage formand a pushrod during delivery.

FIGS. 9A-F are schematic depictions of geometries of other exemplaryslit type septum seals designed to maintain a uniform seal around a drugdosage form and a pushrod during delivery of the drug dosage form.

FIGS. 10A-10D are schematic depictions of an exemplary dispensing devicefor delivering drug dosage forms to the oral mucosa, wherein a means forminimizing saliva influx into the dispensing device during theadministration of the dosage forms to the patient is shown.

FIG. 11A is a schematic depiction of an exemplary dispensing mechanismfor a dispensing device for delivering drug dosage forms, wherein acolumn type dispensing mechanism at a rest position is illustrated. Thedispensing mechanism comprises one or more of a cartridge assembly, anactivation button, a motor, a cam, a desiccant agent, seals, a deliverysensor, a spring clip, and a spring.

FIG. 11B is a schematic depiction of the dispensing device of FIG. 11Awherein the positions of the dispensing mechanism, motor and cam are ata rest position.

FIGS. 11C and 11D are a schematic depiction of the dispensing device ofFIG. 11A wherein the positions of the dispensing mechanism, motor andcam are at a retrieval position.

FIGS. 11E and 11F are a schematic depiction of the dispensing device ofFIG. 11A wherein the positions of the dispensing mechanism, motor andcam are at a dispensing position.

FIGS. 11G and 11H are depictions of the optical sensing mechanism fordetecting delivery of drug dosage forms of the dispensing device. Thedispensing mechanism comprises one or more cartridge assembly, cam,desiccant, seals, delivery sensor, and a spring clip.

FIG. 12A is a schematic depiction of the dispensing end of a push rod3051 used to deliver a drug dosage form 3067 using a dispensing device3011 of the invention.

FIGS. 12B-E provide a schematic depiction of push rod embodiments foruse in a dispensing device of the invention wherein the push rod mayhave transparent and/or reflective portions; the push rod 3051 may beentirely transparent (FIG. 12B); the push rod 3051 may have be opaquewith or without a window 3105 and with or without a reflector 106 (FIG.12C); have a transparent tip portion 3107 and an opaque push rod portion3109 (FIG. 12D); or have a transparent push rod portion 3107 and anopaque tip portion 3109 (FIG. 12E).

FIG. 13A depicts an additional embodiment of a dispensing device of theinvention dispensing mechanism, wherein a ribbon type dispensingmechanism at a rest position is illustrated.

FIG. 13B depicts the dispensing mechanism of FIG. 13A at a retrievalposition.

FIG. 13C depicts the dispensing mechanism of FIG. 13A at a dispensingposition.

FIG. 14 depicts an additional embodiment of a dispensing mechanism of adispensing device of the invention, wherein a ribbon type dispensingmechanism using a different type of a pushrod at dispensing position isillustrated.

FIG. 15A depicts an additional embodiment of a dispensing device of theinvention, wherein a disc type dispensing mechanism at rest position isillustrated.

FIG. 15B depicts the dispensing mechanism of FIG. 13A at a dispensingposition.

FIGS. 16A-16C depict an exemplary pushrod designed for dispensing a drugdosage form.

FIGS. 17 and 18 depict additional exemplary pushrod dispensing devicesof the invention for dispensing a drug dosage form, wherein the pushrodsare designed to be flexible and to afford different geometry.

FIGS. 19A-19D provide schematic depictions of exemplary drug cartridgesincluding barrel, index/springload, snap-out, and track type,respectively.

FIG. 20 is a schematic depiction of an exemplary device showing thestages of push rod/tablet interaction during device use. In FIG. 20, thepush rod 5051, dosage forms 5067, shipping tablet 5069, spring 5073 andposition sensor 5071 are shown. During use, the push rod 5051 movesbetween positions 5057, 5059, 5061, 5063, 5065 and 5067, also shown inFIG. 20.

FIGS. 21A-D provide a series of flow diagrams for use of an exemplarydevice of the invention showing the stages of push rod/tabletinteraction during device use, wherein FIG. 21A shows the LOAD feature;FIG. 21B shows the CALIBRATE feature; FIG. 21C shows the DISPENSEfeature; and FIG. 21D shows the DISASSEMBLE feature.

FIGS. 22A and 22B provide depictions of exemplary drug dosage formshapes. FIG. 22A is a schematic depiction of symmetric drug dosage formsincluding round discs with flat, concave, or convex faces, ellipsoidswith flat, concave, or convex faces, spherical, polygons with 3 or moreedges and flat, concave, or convex faces, or any other curved solidbody. FIG. 22B is a schematic depiction of asymmetric dosage forms.

FIGS. 23A-F provide an illustration of six single dose applicators.

FIG. 24 provides an illustration of a multiple dose applicator where aplurality of single dose applicators are stored prior to use.

FIGS. 25A-C provide an illustration of additional single dose applicatorand multiple dose applicator embodiments.

FIGS. 26A-B provide an illustration of two stages of use of oneembodiment of a single dose applicator.

FIGS. 27A and 27B are schematic depictions of an exemplary single doseapplicator.

FIGS. 28A-C provide an illustration of one type of single doseapplicator and use thereof in delivering a dosage form to a subject.

FIGS. 29A-29D are schematic depictions of an exemplary mechanicallockout means, wherein one exemplary locking mechanism is illustrated.FIGS. 29A through 29D illustrate various stages of the lockout mechanismrelated to dispensing drug dosage forms.

FIGS. 30A-30F are schematic depictions of exemplary lockout devices,such as a pushrod type device (30A), lockout on actuator type device(30B), safety button/latch type device (30C/30D), solenoid type device(30E), and another solenoid type lockout device (30F), respectively.

FIG. 31 is a schematic architecture connection diagram illustrating thevarious components that may be included in a drug dispensing device orsystem including a device with a separate drug dispensing device head280, drug dispensing device body 282, disposable drug dosage cartridge48, a portable docking FOB 296, a patient RFID tag 281, and a basestation 292.

FIG. 32A is a schematic depiction of an exemplary architecture having areusable head, disposable body, and recharge station.

FIG. 32B is a schematic depiction of an exemplary architecture having areusable head, a disposable body, a docking station, and a dockingstation.

FIG. 32C is a schematic depiction of an exemplary architecture having adisposable body, portable docking station (fob), and a recharge station.

FIG. 32D is a schematic depiction of an exemplary architecture having adisposable body and a docking station.

FIG. 32E is a schematic depiction of an exemplary architecture having areusable head, disposable body, portable docking station, and rechargestation.

FIG. 32F is a schematic depiction of an exemplary architecture, whereina fully disposable device is shown.

FIG. 33 is a schematic depiction of the functional elements of the drugdispensing system of the invention, including a drug dispensing deviceand pharmaceutical network with a monitoring and control apparatuscoupled via a wireless or other bi-directional communication network.The system includes a battery powered microprocessor which comprises RAMand ROM, is operably connected to a docking connector, and communicatesin a bi-directional manner with an RFID antenna, a WI/FI antenna,wherein the drug dispensing device and pharmaceutical network furthercomprises, a user interface, an audible alarm, a graphic display, adispensing button and sensor, and a dispensing button lockout.

FIGS. 34A and 34B are block diagrams illustrating communicationassociated with a drug dispensing system of the invention. FIG. 34Adepicts a system communication diagram comprising a radio frequencyidentification (RFID) tag, a dispensing device, a base station/dock anda healthcare provider personal computer. FIG. 34B depicts a systemcommunication diagram comprising an RFID tag, a dispensing device, a fob(or portable handheld docking device) and a healthcare provider personalcomputer.

FIG. 35 is a block diagram of a setup and programming flow chart for adrug dispending system of the invention, wherein the process involvesthe steps of: loading a dosage form cartridge into the dispensingdevice; closing and locking the dispensing device; docking thedispensing device into the PC; programming the dispensing device;recording a thumbprint or PIN to identify the appropriate user; andtesting the dispensing device.

FIG. 36 is a block diagram illustrating a dispensing device operationflow chart, wherein one example of stepwise operation of a drugdispensing device of the invention is provided.

FIG. 37 is a block diagram illustrating another exemplary dispensingdevice operation flow chart, wherein a second example of stepwiseoperation of a drug dispensing device of the invention is provided.

FIG. 38 is a block diagram illustrating another exemplary dispensingdevice operation flow chart, wherein a third example of stepwiseoperation of a drug dispensing device of the invention is provided.

FIG. 39 is a block diagram illustrating exemplary dispensing devicedisassembly flow chart by a healthcare professional, wherein an exampleof stepwise disassembly of a drug dispensing device of the invention,following use, is provided.

FIG. 40 is a block diagram illustrating an exemplary outpatient acutedispensing device operation flow chart, wherein an example of stepwiseoperation of a drug dispensing device of the invention is provided.

FIG. 41 is a block diagram illustrating an exemplary inpatientdispensing device setup and assembly flow chart, wherein an example ofstepwise setup and assembly of a drug dispensing device of theinvention, prior to use, is provided.

FIG. 42 is a block diagram illustrating an exemplary outpatient chronicdispensing device setup and assembly flow chart, wherein an example ofsetup and assembly operation of a drug dispensing device of theinvention is provided.

FIG. 43 is a graphic depiction of sufentanil plasma concentrationsfollowing intravenous dosing or sublingual single dose administration ofthree different strengths of sufentanil dosage forms in healthy humanvolunteers (n=12).

FIG. 44 is a graphic depiction of sufentanil plasma concentrationsfollowing sublingual administration of a sufentanil formulation #44(equivalent to human #47 formulation; n=3) compared to intravenoussufentanil administration (n=3) in a healthy, conscious Beagle dogmodel. Error bars represents standard errors around the mean (SEM).

FIG. 45 is a graphic depiction of sufentanil plasma concentrationsfollowing sublingual administration of a sufentanil solution (n=6) orfollowing oral ingestion of a sufentanil (n=6) compared to intravenousadministration of sufentanil (n=3) in a healthy, conscious Beagle dogmodel. Error bars represents ±standard error around the mean (SEM).

FIG. 46 is a graphic depiction of alfentanil plasma concentrationsfollowing sublingual administration of an alfentanil NanoTab® (n=2)compared to intravenous alfentanil administration (n=3) in a healthy,conscious Beagle dog model. Error bars represents ±standard error aroundthe mean (SEM).

DETAILED DESCRIPTION I. Introduction

Provided herein are compositions, methods, systems and kits for oraltransmucosal administration of opioid-containing small volume dosageforms using a device. Oral transmucosal delivery of the dosage formsminimizes the saliva response and therefore minimizes delivery of thedrug to the GI tract, such that the majority of drug is delivered acrossthe oral mucosa. The small volume dosage forms have bioadhesiveproperties which facilitate adherence to the oral mucosa, thusminimizing the risk of ingestion and inefficient delivery due toswallowing.

The following disclosure describes the dosage forms, devices, methods,systems and kits which constitute the invention. The invention is notlimited to the specific dosage forms, devices, methodology, systems,kits or medical conditions described herein, as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise. Thus, for example, reference to“a drug formulation” includes a plurality of such formulations andreference to “a drug delivery device” includes systems comprising drugdosage forms and devices for containment, storage and delivery of suchdosage forms.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood to one ofordinary skill in the art to which this invention belongs. Although anymethods, devices and materials similar or equivalent to those describedherein can be used in the practice or testing of the invention, thepreferred methods, devices and materials are now described.

All publications mentioned herein are incorporated herein by referencein their entirety for the purpose of describing and disclosing thecompositions and methodologies which are described in the publicationswhich might be used in connection with the presently describedinvention. The publications discussed herein are provided solely fortheir disclosure prior to the filing date of the present application.Nothing herein is to be construed as an admission that the invention isnot entitled to antedate such a disclosure by virtue of prior invention.

II. Definitions

The term “active agent” or “active” may be used interchangeably hereinwith the term “drug” and is meant to refer to any therapeutically activeagent.

The term “adhere” is used herein with reference to a drug dosage form orformulation that is in contact with a surface such as a mucosal surfaceand is retained on the surface without the application of an externalforce. The term “adhere” is not meant to imply any particular degree ofsticking or bonding, nor is it meant to imply any degree of permanency.

The term “drug” as used herein is generally meant to refer to anysubstance that alters the physiology of an animal. The term “drug” maybe used interchangeably herein with the terms “therapeutic agent”,“medication”, “pharmacologically active agent” and the like. It will beunderstood that a “drug” formulation of the invention may include morethan one therapeutic agent, wherein exemplary combinations oftherapeutic agents include a combination of two or more drugs.

The term “analgesic drug” as used herein includes sufentanil or asufentanil congener, such as alfentanil, fentanyl, lofentanil,carfentanil, remifentanil, trefentanil, or mirfentanil, as well asformulations comprising one or more therapeutic compounds. Use of thephrase “sufentanil or a congener” is not meant to be limiting to use of,or formulations comprising, only one of these selected opioid compounds.Furthermore, reference to sufentanil alone or to a selected sufentanilcongener alone, e.g., reference to “alfentanil”, is understood to beonly exemplary of the drugs suitable for delivery according to themethods of the invention, and is not meant to be limiting in any way.

The term “AUC” as used herein means “area under the curve” in a plot ofconcentration of drug in plasma versus time. AUC is usually given forthe time interval zero to infinity, however, clearly plasma drugconcentrations cannot be measured ‘to infinity’ for a patient somathematical approaches are used to estimate the AUC from a limitednumber of concentration measurements. In a practical sense, the AUC(from zero to infinity) represents the total amount of drug absorbed bythe body, irrespective of the rate of absorption. This is useful whentrying to determine whether two formulations of the same dose releasethe same dose of drug to the body. The AUC of a transmucosal dosage formcompared to that of the same dosage administered intravenously serves asthe basis for a measurement of bioavailability.

The term “bioadhesion” as used herein refers to adhesion to a biologicalsurface including mucosal membranes.

The term “bioavailability” or “F” as used herein means “percentbioavailability” and represents the fraction of drug absorbed from atest article as compared to the same drug when administeredintravenously. It is calculated from the AUC_(∞) of the test articlefollowing delivery via the intended route versus the AUC_(∞) for thesame drug after intravenous administration. It is calculated from theequation: Bioavailability (%)=AUC_(∞) (test article)/AUC_(∞)(intravenous route/article).

The term “breakthrough pain” as used herein, is a transitory flare ofpain of moderate to severe intensity occurring on a background ofotherwise controlled pain. “Breakthrough pain” can be intense for shortperiods of time, as short as 1 or 2 minutes or as long as 30 minutes ormore.

The term “cartridge” is used herein with reference to a replaceable,single use disposable cartridge configured to hold one or more drugdosage forms, typically, one up to 200 drug dosage forms. The cartridgetypically comprises a smart cartridge recognition system with a physicalkeyed feature on the cartridge, a bar code on the cartridge, a magnetictag on the cartridge, an RFID tag on the cartridge, an electronicmicrochip on the cartridge, or a combination thereof. The cartridge maycomprise one or more shipping tablets wherein at least one shippingtablet is dispensed prior to dispensing of a dosage form.

The term “C_(max)” as used herein means the maximum observed plasmaconcentration following administration of a drug.

The term “congener” as used herein refers to one of many variants orconfigurations of a common chemical structure.

The term “disintegration” is used interchangeably herein with “erosion”and means the physical process by which a dosage form breaks down andpertains to the physical integrity of the dosage form alone. This canoccur in a number of different ways including breaking into smallerpieces and ultimately, fine and large particulates or, alternatively,eroding from the outside in, until the dosage form has disappeared.

The term “dispensing device”, “drug dispensing device”, “dispenser”,“drug dispenser”, “drug dosage dispenser”, “device” and “drug deliverydevice” are used interchangeably herein and refer to a device thatdispenses a drug dosage form. The dispensing device provides forcontrolled and safe delivery of a pharmaceutically active substance(e.g., an opioid such as sufentanil) formulated in the dosage form. Thedevice may be adapted for storage and/or delivery of a dosage form suchas a lozenge, pill, tablet, capsule, membrane, strip, liquid, patch,film, gel, spray or other form.

The term “reservoir” refers to a chamber or containment space within adelivery or storage device for storing a formulation to be deliveredfrom the delivery device.

The term “dispensing end” as used herein with reference to a devicemeans the portion of the device comprising the proboscis and shroudwhich serves to deliver a drug dosage form to the oral mucosa of asubject.

The term “drug”, “medication”, “pharmacologically active agent”,“therapeutic agent” and the like are used interchangeably herein andgenerally refer to any substance that alters the physiology of an animaland can be effectively administered by the oral transmucosal route.

The term “erosion time” means the time required for a solid dosage formto break down until the dosage form has disappeared.

“Operatively connected” as used herein means the components are providedin a device so as to function as intended to achieve an aim. Forexample, a memory device operatively connected to a CPU which is furtheroperatively connected to a release mechanism may be meant to indicatethat, upon actuation, the CPU communicates with the memory device tocheck the status or history of drug delivery, and then furthercommunicates with the release mechanism (e.g., via a solenoid and aswitch) to release and dispense a drug.

The term “FOB” refers to a small, portable handheld, powered electronicdocking device that can be used in conjunction with the drug dispensingdevice to upload data, download data, control access to the drugdispensing device, control access to the drug dosage forms, or enhanceor otherwise alter the user interface of the drug dispensing device. AFOB may communicate and dock with a drug dispensing device either in awired or wireless fashion. A FOB may be adapted to attach to a cord soas to allow the FOB to hang from the neck of a healthcare professionalsuch as a physician or caregiver, particularly in the hospital setting.A drug dispensing device may communicate with the physician or caregiver via the FOB.

The terms “formulation” and “drug formulation” as used herein refer to aphysical composition containing at least one pharmaceutically activesubstance, which may be provided in any of a number of dosage forms fordelivery to a subject. The dosage form may be provided to the patient asa lozenge, pill, capsule, membrane, strip, liquid, patch, film, gum,gel, spray or other form.

The term “hydrogel-forming preparation”, means a solid formulationlargely devoid of water which upon contact with an aqueous solution,e.g., a bodily fluid, and in particular that of the oral mucosa, absorbswater in such a way that it forms a hydrated gel in situ. The formationof the gel follows unique disintegration (or erosion) kinetics whileallowing for release of the therapeutic agent over time.

The term “lock-out feature” is used herein with reference to a featureof the device which provides for a “lock-out time”.

The term “lock-out time” is used herein with reference to the period oftime during which the device does not allow drug accessibility, i.e., adosage form cannot be dispensed during the “lock-out time”. “Lock-outtime” may be programmable, a fixed time interval, a predeterminedinterval, a predetermined variable interval, an interval determined byan algorithm or a variable interval communicated to the device from aremote computer or docking station.

The term “LogP” as used herein means logarithm of the ratio ofequilibrium concentrations of un-ionized compound between octanol andwater. P also called the “octanol-water partition coefficient” andserves as a means to quantify the hydrophiobicity or lipophilicity of, achemical characteristic of a given drug.

The term “mucoadhesion” is used herein in to refer to the adhesion tomucosal membranes which are covered by mucus, such as those in the oralcavity and may be used interchangeably herein with the term“bioadhesion” which refers to adhesion to any biological surface.

The term “mucosal membrane” refers generally to any of the mucus-coatedbiological membranes in the body. Absorption through the mucosalmembranes of the oral cavity is of particular interest. Thus, oralmucosal absorption, i.e., buccal, sublingual, gingival and palatalabsorption are specifically contemplated.

The term “mucosal-depot” is used herein in its broadest sense to referto a reservoir or deposit of a pharmaceutically active substance withinor just beneath the mucosal membrane.

The term “non-ordered particulate mixture” or “non-ordered mixture” isused herein with reference to a formulation where the mixture is notordered with respect to the pharmaceutically active agent and thebioadhesive material or bioadhesion promoting agent, or otherformulation components. In addition, it is used herein with reference toany formulation prepared by a process that involves dry mixing whereindrug particles are not uniformly distributed over the surface of largercarrier particles. Such ‘non-ordered’ mixing may involve dry mixing ofparticles in a non-ordered fashion, where there is no requirement withrespect to the order of addition/mixing of specific excipients with thedrug, bioadhesive material or bioadhesion promoting agent and/ordisintegrants. Further in the non-ordered mixing process, there is nolimitation on the size of the drug particles. The drug particles may belarger than 25 μm. In addition, a “non-ordered mixture” includes anymixing processes in which the primary carrier particles do notincorporate a disintegrant within. Finally the “non-ordered mixture” maybe prepared by any ‘wet mixing’ processes, i.e. processes in which asolvent or non-solvent is added during the mixing process or any mixingprocess in which the drug is added in a solution or suspension form.

The term “operatively connected” as used herein means the components areprovided in a device so as to function as intended to achieve an aim.For example, a memory device operatively connected to a CPU which isfurther operatively connected to a release mechanism may be meant toindicate that, upon actuation, the CPU communicates with the memorydevice to check the status or history of drug delivery, and then furthercommunicates with the release mechanism (e.g., via a solenoid and aswitch) to release and dispense a drug.

The terms “oral transmucosal dosage form” and “drug dosage form” may beused interchangeably herein and refer to a dosage form which comprises apharmaceutically active substance, e.g., a drug such as sufentanil. Theoral dosage form is used to deliver the pharmaceutically activesubstance to the circulation by way of the oral mucosa and is typicallya “sublingual dosage form”, but in some cases other oral transmucosalroutes may be employed. The dosage form provides for delivery of thepharmaceutically active substance across the oral mucosa and bycontrolling the formulation the timing for release of thepharmaceutically active substance can be achieved. The dosage formcomprises pharmaceutically acceptable excipients and may be referred toas a NanoTab™, as detailed in U.S. application Ser. No. 11/650,174,expressly incorporated by reference herein. The dosage form comprises aformulation that is neither effervescent nor does it comprise anessentially water-free, ordered mixture of microparticles of drugadhered to the surface of carrier particles, where the carrier particlesare substantially larger than the microparticles of drug.

The terms “oral transmucosal drug delivery” and “oral transmucosaladministration” as used herein refer to drug delivery that occurssubstantially via the transmucosal route and not via swallowing followedby GI absorption. Maximal delivery occurs via the oral mucosa, typicallyby placement of the dosage form within the sublingual cavity.

The term “proboscis” is used interchangeably with the terms “dispensingtip” a “delivery tip”, and refers to a dispensing and/or positioning tipof a drug dosage form dispenser that delivers a dosage form to the oralmucosa (e.g., the sublingual space).

The term “acute pain”, and a means for identifying an individual patientfor controlled drug access.

The term “chronic pain” is used herein with reference to pain that istypically present for longer than one month.

The term “radio frequency identification device” or “RFID” is used withreference to an automatic identification method, which relies on storingand remotely retrieving data using devices called RFID tags, wherein theRFID tag is applied to, or incorporated into a product, or person forthe purpose of identification using radiowaves. Some tags can be readfrom several meters away and beyond the line of sight of the reader.

The term “replaceable, single use disposable cartridge” is used withreference to a cartridge for housing drug dosage forms which istypically configured to hold up to 200 drug dosage forms, wherein thecartridge is designed to be used one time and discarded.

The term “shipping tablet” is used herein with reference to an“initialization”, or “shipping” tablet which is the same size and shapeas a drug-containing dosage form but does not contain a pharmaceuticallyactive substance. The “shipping tablet” may comprise a placebo dosageform that does not contain a pharmaceutically active substance or may bemade of plastic or other material. It is the first thing dispensed froma new cartridge after insertion into a dispensing device. The device hasa means for differentiating between the shipping tablet and a dosageform containing a pharmaceutically active substance.

The term “shroud” is used to describe a partial or complete covering ofthe dispensing end of the device which protects the delivery port fromcontact with saliva or other moisture in the oral cavity and forms abarrier between the device, the oral mucosa and tongue, has a relief fordosage form delivery, and an interior that is hydrophobic or hydrophilicwhich serves to minimize or eliminate saliva ingress or moistureingress. The “shroud” creates a barrier from the oral mucosa contactingthe valve area and dosage form, aiding in dosage form dispensing anddiscouraging dosage form adherence to the shroud. The shroud may have arounded interior surface or other geometry to stop the dosage formadhering to the shroud. The shroud limits the ability of the tongue orsublingual mucosa to contact the dosage form dispensing area, therebycontrolling saliva contact and ingress.

The term “subject” includes any subject, generally a mammal (e.g.,human, canine, feline, equine, bovine, ungulate etc.), adult or child,in which treatment for a disorder is desired. The terms “subject” and“patient” may be used interchangeably herein.

The term “systems that include a drug dosage form and a dispensingdevice” as used herein refers to a drug dispensing system for deliveryand/or monitoring of drug administration. The system may be used tomonitor and deliver a pharmaceutically active substance, e.g., an opioidsuch as sufentanil, wherein the amount of drug delivered, correspondingefficacy and safety are enhanced over currently available systems. Thesystem may have one or more features that provide for improved safetyand ease of use over currently available systems including a securityfeature that prevents unauthorized access to the stored drugs, a dosinglock-out feature, a means for identifying an individual patient forcontrolled drug access, a dose counting feature, a memory means forretaining information about dose delivery, and an interface forbidirectional exchange of information with a user, a drug cartridge, oranother device such as a computer.

The term “small volume drug dosage form” or “small volume dosage form”is used herein with reference to a small volume dosage form that has avolume of less than 100 μl and a mass of less than 100 mg. Morespecifically, the dosage form has a mass of less than 100 mg, 90 mg, 80mg, 170 mg, 60 mg, 50 mg, 40 mg, 30 mg, 29 mg, 28 mg, 27 mg, 26 mg, 25mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg or 5 mg ora volume of less than 100 μl, 90 μl, 80 μl, 70 μl, 60 μl, 50 μl, 40 μl,30 μl, 29 mg, 28 mg, 27 μl, 26 μl, 25 μl, 24 μl, 23 μl, 22 μl, 21 μl, 20μl, 19 μl, 18 μl, 17 μl, 16 μl, 15 μl, 14 μl, 13 μl, 12 μl, 11 μl, 10μl, 9 μl, 8 μl, 7 μl, 6 μl or 5 μl. The “dosage form” may or may nothave bioadhesive characteristics and may form a hydrogel upon contactwith an aqueous solution.

The “dosage form” may be used to deliver any drug that can beadministered by the oral transmucosal route in an amount amenable toadministration via the small size of the dosage form, i.e. 0.25 μg to99.9 mg, 1 μg to 50 mg or 1 μg to 10 mg.

The term “small volume sufentanil-containing drug dosage form” is usedherein with reference to a small volume dosage form that contains a doseof sufentanil selected from about 2 micrograms (mcg) to about 200 mcg ofsufentanil, e.g., 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg,60 mcg, 70 mcg, 80 mcg or 100 mcg of sufentanil.

The term “solid dosage form” or “solid drug dosage form” is used hereinwith reference to a small volume dosage form that is a solid, e.g., alozenge, a pill, a tablet, a membrane or a strip.

The term “sublingual”, means literally “under the tongue” and refers toadministering a drug dosage form via the mouth in such a way that thepharmaceutically active substance is rapidly absorbed via the bloodvessels under the tongue rather than via the digestive tract. Absorptionoccurs via the highly vascularized sublingual mucosa and allows thepharmaceutically active substance more direct access to the bloodcirculation, providing for direct systemic administration independent ofGI influences.

The term “treatment” or “management” of a medical disorder or conditionis used herein to generally describe regression, suppression, ormitigation of symptoms of the medical disorder or condition so as tomake the subject more comfortable as determined by subjective criteria,objective criteria, or both.

The term “diversion” is used here to generally describe the act or aninstance of diverting the use of a dispensing device and/or drug dosageforms therein from the intended patient to any other unauthorized orunintended individual, whether it is accidental or intentionaldiversion.

The term “Therapeutic Time Ratio” or “TTR” presents the average timethat the drug is present at therapeutic levels, defined as time withinwhich the drug plasma concentration is maintained above 50% of C_(max)normalized by the drug's elimination half-life and it is calculated bythe formula: TTR=(Time above 50% of C_(max))/(Terminal intravenouselimination half-life of the drug). The last term is obtained fromliterature data for the drug of interest in the appropriate species.

The term “T_(max)” as used herein means the time point of maximumobserved plasma concentration.

The term “T_(onset)” as used herein means the observed “time of onset”and represents the time required for the plasma drug concentration toreach 50% of the maximum observed plasma concentration, C_(max).

The term “therapeutically effective amount” means an amount of atherapeutic agent, or a rate of delivery of a therapeutic agent (e.g.,amount over time), effective to facilitate a desired therapeutic effect,such as pain relief. The precise desired therapeutic effect (e.g., thedegree of pain relief, and source of the pain relieved, etc.) will varyaccording to the condition to be treated, the tolerance of the subject,the drug and/or drug formulation to be administered (e.g., the potencyof the therapeutic agent (drug), the concentration of drug in theformulation, and the like), and a variety of other factors that areappreciated by those of ordinary skill in the art.

The term “transmucosal” delivery of a drug and the like is meant toencompass all forms of delivery across or through a mucosal membrane. Inparticular, “oral transmucosal” delivery of a drug includes deliveryacross any tissue of the mouth, pharynx, larynx, trachea, or uppergastrointestinal tract, particularly including the sublingual, gingivaland palatal mucosal tissues.

III. Drug Dosage Forms

The claimed small volume oral transmucosal drug dosage forms produce areduced saliva response as compared with conventional, larger dosageforms that are intended to deliver a drug in the oral cavity. The dosageforms contain a pharmaceutically active substance and provide for highabsorption rates of the pharmaceutically active substance across theoral mucosa and reduced uptake via the gastrointestinal tract, therebyoffering a more consistent and reproducible pharmacokinetic andcorresponding pharmacodynamic profile.

The dosage forms are typically a “sublingual dosage form”, but in somecases other oral transmucosal routes may be employed. The dosage form isa substantially homogeneous composition which comprises one or moreactive drugs together with pharmaceutically acceptable excipients.

The preferred site for oral transmucosal drug delivery is the sublingualarea, although in certain embodiments it may be advantageous for thedosage form to be placed inside the cheek, or to adhere to the roof ofthe mouth or the gum.

Sublingual delivery is preferred as the sublingual mucosa is morereadily permeable to medications than other mucosal areas, such as thebuccal mucosa, resulting in more rapid uptake.

The dosage forms provide for the delivery of a greater percentage (andamount) of the drug via the oral mucosa and a corresponding decrease indelivery via the gastrointestinal (GI) tract as compared to traditionaloral dosage forms and other oral transmucosal dosage forms.

Typically, the dosage forms are generally adapted to adhere to the oralmucosa (i.e. are bioadhesive) during the period of drug delivery, anduntil most or all of the drug has been delivered from the dosage form tothe oral mucosa.

The claimed dosage forms have a mass of less than 100 mg and a volume ofless than 100 μl. More specifically, the dosage forms have a mass ofless than 100 mg, 90 mg, 80 mg, 170 mg, 60 mg, 50 mg, 40 mg, 30 mg, 29mg, 28 mg, 27 mg, 26 mg, 25 mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg, 19mg, 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg,8 mg, 7 mg, 6 mg or 5 mg or a volume of less than 100 μl, 90 μl, 80 μl,70 μl, 60 μl, 50 μl, 40 μl, 30 μl, 29 mg, 28 mg, 27 μl, 26 μl, 25 μl, 24μl, 23 μl, 22 μl, 21 μl, 20 μl, 19 μl, 18 μl, 17 μl, 16 μl, 15 μl, 14μl, 13 μl, 12 μl, 11 μl, 10 μl, 9 μl, 8 μl, 7 μl, 6 μl or 5 μl. Thedosage forms typically have bioadhesive characteristics and may form ahydrogel upon contact with an aqueous solution.

The dosage forms typically have an erosion time of from 30 seconds up to5 minutes, up to 10 minutes, up to 15 minutes or up to 30 minutes.

In general, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 98% or at least 99% of the total amount of pharmaceutically activesubstance in a dosage form administered to the oral mucosa of a subjectis absorbed via the oral transmucosal route.

The dosage forms may have essentially any shape, examples of whichinclude a round disc with a flat, concave, or convex face, an ellipsoidshape, a spherical shape, a polygon with three or more edges and flat,concave, or convex faces. The dosage forms may be symmetrical orasymmetrical, and may have features or geometries that allow forcontrolled, convenient, and easy storage, handling, packaging or dosing.

Oral transmucosal drug delivery is simple, non-invasive, and can beadministered by a caregiver or patient with minimal discomfort. A dosageform for oral transmucosal delivery may be solid or non-solid. In onepreferred embodiment, the dosage from is a solid that turns into ahydrogel following contact with saliva. In another preferred embodiment,the dosage from is a solid that erodes without forming a hydrogelfollowing contact with saliva.

Generally, oral transmucosal delivery of pharmaceutically activesubstances is achieved using solid dosage forms such as lozenges ortablets, however, liquids, sprays, gels, gums, powders, and films andthe like may also be used.

For certain drugs, such as those with poor bioavailability via the GItract, e.g., lipophilic opioids such as sufentanil and alfentanil, oraltransmucosal delivery is a more effective delivery route than GIdelivery. For such lipophilic drugs, oral transmucosal delivery has ashorter onset time (i.e., the time from administration to therapeuticeffect) than does oral GI delivery and provides better bioavailabilityand more consistent pharmacokinetics.

The claimed drug dosage forms are designed and adapted to reduce thesaliva response, thus reducing the amount of drug swallowed, and therebydelivering a substantial amount of drug to a subject via the oralmucosa. The claimed drug dosage forms also provide efficacious deliveryof drug via the oral mucosa and a consistent plasma level within thetherapeutic window.

The claimed dosage forms comprise substantially homogeneous formulationswhich include at least 0.001% percent by weight of the pharmaceuticallyactive substance in combination with pharmaceutically acceptableexcipients. Typically the claimed dosage forms comprise from 0.01-99% orfrom about 0.25 μg to 99.9 mg, from about 1 μg to 50 mg or from about 1μg to 10 mg w/w of the pharmaceutically active substance.

Formulations for preparation of the claimed dosage forms and methods ofmaking them are described in U.S. application Ser. Nos. 11/825,251 and11/650,227, expressly incorporated by reference herein. An exemplaryformulation is bioadhesive and comprises from about 0.0004% to about0.04% sufentanil, e.g., 0.0005%, 0.001%, 0.002%, 0.003%, 0.004%, 0.006%,0.008%, 0.01%, 0.012%, 0.014% or 0.016% sufentanil. In general, theformulation comprises (a) a non-ordered mixture of a pharmaceuticallyactive amount of a drug; (b) a bioadhesive material which provides foradherence to the oral mucosa of the subject; and (c) stearic acid,wherein dissolution of a dosage form comprising the formulation isindependent of pH, e.g., over a pH range of about 4 to 8.

Numerous suitable nontoxic pharmaceutically acceptable carriers for usein oral dosage forms can be found in Remington's PharmaceuticalSciences, 17th Edition, 1985.

It will be understood that the formulation is converted into a dosageform for delivery to a subject using procedures routinely employed bythose of skill in the art, such as direct compression, wet granulation,etc. The process for preparation of the dosage form is optimized foreach formulation in order to achieve high dose content uniformity.

While not wishing to be bound by theory, when a claimed dosage form isplaced in the sublingual cavity, preferably under the tongue on eitherside of the frenulum linguae, it adheres upon contact. As the dosageform is exposed to the moisture of the sublingual space the dosage formabsorbs water, resulting in erosion of the dosage form and release ofthe active drug to the circulation of the subject.

IV. Sufentanil

Opioids are widely used for the treatment of pain, and are generallydelivered intravenously, orally, epidurally, transdermally, rectally andintramuscularly. Morphine and its analogues are commonly deliveredintravenously and are effective against severe, chronic and acute pain.However, they can also have severe respiratory depressive effects if notused appropriately and also suffer from a high abuse potential. Thepredominant cause of morbidity and mortality from pure opioid overdosesis due to respiratory complications.

One exemplary use of the claimed drug dosage forms is with applicationto pain-relief. When the claimed drug dosage forms are used fortreatment of pain, they comprise a drug such as an opioid or opioidagonist and are utilized to treat both acute and chronic pain ofmoderate to severe intensity.

The active agent in such drug dosage forms is sufentanil or a sufentanilcongener such as alfentanil, fentanyl, lofentanil, carfentanil,remifentanil, trefentanil, or mirfentanil. In a preferred embodiment,sufentanil is the active agent. Sufentanil may be provided in theclaimed dosage forms in any of a number of formulations, e.g., assufentanil citrate or as sufentanil base.

Another preferred embodiment relies on a sufentanil congener as theactive agent. Yet another preferred embodiment relies on a combinationof sufentanil and at least one additional agent for treatment ofanalgesia as the active agent, e.g., a combination of sufentanil andalfentanil. Various opioid drugs have different pharmacokinetic profilesand different interactions with mu opioid receptor splice variants and,therefore, may be used in combination to enhance the therapeutic effect.

Sufentanil(N-[(4-(Methoxymethyl-1-(2-(2-thienyl)ethyl)-4-piperidinyl)]-N-phenylprop-anamide),is used as a primary anesthetic, to produce balanced general anesthesiain cardiac surgery, for epidural administration during labor anddelivery and has been administered experimentally in both intranasal andliquid oral formulations. A commercial form of sufentanil used for IVdelivery is the SUFENTA FORTE® formulation. This liquid formulationcontains 0.075 mg/ml sufentanil citrate (equivalent to 0.05 mg ofsufentanil base) and 9.0 mg/ml sodium chloride in water. It has a plasmaelimination half-life of 148 minutes, and 80% of the administered doseis excreted in 24 hours.

Following transbuccal administration of fentanyl using a lozenge (e.g.,Actiq®), the bioavailability is 50%, although the T_(max) for the 200mcg dosage of Actiq® ranges from 20-120 minutes resulting from erraticGI uptake due to the fact that 75% of the fentanyl is swallowed (Actiq®package insert). More recent publications on the T_(max) of Actiqindicate that these original times were skewed towards more rapid onset(Fentora package insert indicates a range of T_(max) for Actiq extendingup to 240 minutes). Fentora (a fentanyl buccal tablet) exhibits abioavailability of 65%, with reported swallowing of 50% of the drug. Incontrast to the claimed dosage forms, both Actiq® and Fentora sufferfrom the disadvantage that substantial amounts of lozenge-administeredfentanyl are swallowed by the patient.

Although sufentanil and fentanyl have many similarities as potentmu-opioid receptor agonists, they have been shown to differ in many keyways. Multiple studies have demonstrated sufentanil to be in the rangeof 7-24 times more potent than fentanyl (SUFENTA® package insert; PaixA, et al. Pain, 63:263-69, 1995; Reynolds L, et al., Pain, 110:182-188,2004). Therefore, sufentanil may be administered using a smaller dosageform, avoiding the increased saliva response of a larger dosage form andthereby minimizing the amount of drug that is swallowed. This leads tominimal GI uptake.

In addition, fentanyl and other opiate agonists, have the potential fordeleterious side effects including respiratory depression, nausea,vomiting and constipation. Since fentanyl has a 30% bioavailability fromthe GI route, this swallowed drug can contribute to the C_(max) plasmalevels to a significant degree and results in the erratic C_(max) andT_(max) observed with these products.

Further, the lipid solubility (octanol-water partition coefficient) ofsufentanil (1778:1) is greater than fentanyl (816:1). Sufentanil alsodisplays increased protein binding (91-93%) compared with fentanyl(80-85%) (SUFENTA® and Actiq® package inserts, respectively). Sufentanilhas a pKa of 8.01, whereas the pKa of fentanyl is 8.43 (Paradis et al.,Therapeutic Drug Monitoring, 24:768-74, 2002). These differences canaffect various pharmacokinetic parameters, for example, sufentanil hasbeen shown to have a faster onset of action and faster recovery timesthan fentanyl (Sanford et al., Anesthesia and Analgesia, 65:259-66,1986). As compared to fentanyl, use of sufentanil can result in morerapid pain relief with the ability to titrate the effect and avoidoverdosing.

Importantly, sufentanil has been shown to produce endocytosis of themu-opioid receptor 80,000 times more potently than fentanyl (Koch etal., Molecular Pharmacology, 67:280-87, 2005). The result of thisreceptor internalization is that neurons continue to respond tosufentanil more robustly over time than with fentanyl, suggesting thatclinically less tolerance would develop to sufentanil compared tofentanyl with repeated dosing.

The use of sufentanil clinically has predominantly been limited to IVadministration in operating rooms or intensive care units. There havebeen a few studies on the use of liquid sufentanil preparations forlow-dose intranasal administration (Helmers et al., 1989; Jackson K, etal., J Pain Symptom Management 2002: 23(6): 450-452) and case reports ofsublingual delivery of a liquid sufentanil preparation (Gardner-Nix J.,J Pain Symptom Management. 2001 August; 22(2):627-30; Kunz K M, TheisenJ A, Schroeder M E, Journal of Pain and Symptom Management, 8:189-190,1993). In most of these studies, the smallest dosing of sufentanil inadults was 5 mcg in opioid naive patients. Liquid administered to theoral or nasal mucosa suffers from lower bioavailability and possibly ashorter duration of action as demonstrated by the animal studies(sublingual liquid) described herein, as well as the literature (nasalliquid drops—Helmers et al., 1989). Gardner-Nix provides analgesic data(not pharmacokinetic data) produced by liquid sublingual sufentanil anddescribes the analgesic onset of liquid sublingual sufentanil occurringwithin 6 minutes but the duration of pain relief lasted onlyapproximately 30 minutes.

Prior to the work of the current inventors, no pharmacokinetic data hadbeen published on sublingual sufentanil in any form.

The claimed drug dosage forms contain from about 0.25 to about 200 mcgof sufentanil per dosage form for oral transmucosal delivery. In oneexemplary embodiment, each dosage form contains from about 0.25 to about200 mcg of sufentanil, alone or combination with one or more othertherapeutic agents or drugs.

Exemplary drug dosage forms for administration to children (pediatricpatients) contain from about 0.25 to about 120 mcg of sufentanil perdosage form. For example, a drug dosage form for administration tochildren may contain about 0.25, 0.5, 1, 2.5, 4, 5, 6, 8, 10, 15, 20,40, 60 or 120 mcg of sufentanil for oral transmucosal delivery. Itfollows that for pediatric patients, an exemplary dose range is from atleast about 0.02 mcg/kg to about 0.5 mcg/kg with a preferable range offrom about 0.05 to about 0.3 mcg/kg.

Exemplary drug dosage forms for administration to adults contain fromabout 2.5 to about 200 mcg of sufentanil per dosage form. For example, adrug dosage form for administration to adults may contain about 2.5, 3,5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 180 or 200 mcg or more ofsufentanil for oral transmucosal delivery.

Preferably, a sufentanil-containing dosage form comprises from about 2to about 200 micrograms (mcg) of sufentanil, e.g., 5 mcg, 10 mcg, 15mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 60 mcg, 70 mcg or 80 mcg ofsufentanil.

As will be understood by those of skill in the art, the dose will be onthe low end of the range for children and the high end of the range foradults dependent upon body mass, in particular when administered longterm to opioid-tolerant adults. Prior to the work of the currentinventors, small-volume oral transmucosal drug delivery dosage forms ofsufentanil have not been described.

In various embodiments, the claimed dosage forms provide effective painrelief in all types of patients including children, adults of all ageswho are opioid tolerant or naive and non-human mammals. The inventionfinds utility in both the inpatient and outpatient setting and in thefield.

V. Congeners of Sufentanil

Congeners of sufentanil find use in the compositions, methods andsystems described herein, examples of which include remifentanil andalfentanil.

In certain embodiments, the dosage form comprises at least 0.005% to asmuch as 99.9% by weight of alfentanil, lofentanil, carfentanil,remifentanil, trefentanil or mirfentanil. The percentage of activeingredient(s) will vary dependent upon the size of the dosage form andnature of the active ingredient(s), optimized to obtain maximal deliveryvia the oral mucosal route. In some aspects more than one activeingredient may be included in a single dosage form.

Remifentanil is a potent sufentanil congener that is metabolized muchmore rapidly than fentanyl or sufentanil, but may be suitable fortreatment of acute pain when delivered via a sustained-releaseformulation. A remifentanil-containing dosage form typically comprisesfrom about 0.25 mcg to 99.9 mg of remifentanil. The dose ranges for theremifentanil formulation may include 0.1 mcg/kg-50 mcg/kg over a timeperiod of 20 minutes, for example, for both adult and pediatricpatients. These dosages may be repeated at appropriate time intervals,which may be shorter than the time intervals for fentanyl or sufentanil.

Alfentanil is also a potent sufentanil congener that is rapidlymetabolized but may be suitable for use in a sustained-releaseformulation. The dosage forms may contain from about 10 to about 10000mcg of alfentanil per dosage form for oral transmucosal delivery. Aswill be understood by those of skill in the art, the dose will be on thelow end of the range for children and the high end of the range foradults dependent upon body mass, in particular when administered longterm to opioid-tolerant adults.

Exemplary dosage forms for administration to children (pediatricpatients) contain from about 10 to about 6300 mcg of alfentanil perdosage form. For example, a dosage form for administration to childrenmay contain about 10, 25, 50, 130, 210, 280, 310, 420, 600, 780, 1050,2100, 3000 or 6300 mcg of alfentanil for oral transmucosal delivery.

Exemplary dosage forms for administration to adults contain from about70 to about 10000 mcg of alfentanil per dosage form. For example, adosage form for administration to adults may contain about 70, 140, 160,210, 280, 310, 420, 600, 780, 1050, 2100, 3000, 6300 or 10000 mcg ormore of alfentanil for oral transmucosal delivery.

Following delivery of a single dose of a sufentanil-, alfentanil-, orremifentanil-containing dosage form to a human subject, the plasma levelof sufentanil, alfentanil or remifentanil may reach a maximum levelwithin 60 minutes, e.g., between 5 and 50 minutes or between 10 and 40minutes following administration.

VI. Treatment of Pain

Patients suffering from chronic painful conditions can also haveintermittent exacerbations of their pain, requiring acute use offast-acting breakthrough opioids in addition to their use of slow-onsettime-release opioids for their baseline chronic pain.

Breakthrough pain or procedural pain can be intense for short periods oftime, as short as 1 or 2 minutes or as long as 30 minutes or more,therefore there would be a significant advantage in providing an opioidformulation that produced more rapid clinically effective plasma levelswith a more consistent and predictable period of effect, but also had alimited half-life to avoid excessive opioid dosing for short durationpain events.

Opioids remain the most powerful from of analgesics, however, improvedforms are needed that have minimal side effects, and can be provided ina manner in which patient use can be easily tracked by the physician.

Using current treatment methods, pain control is attempted using anumber of interventions, which generally include: patient-controlledanalgesia (PCA), continuous epidural infusion (CEI), other types ofacute pain control, palliative care pain control, and home healthpatient pain control. These methods meet with varying degrees of successwith respect to duration of control, ease of treatment and safety versusside effects.

The need for rapid treatment of acute pain occurs in many differentclinical situations, including post-operative recuperation, rheumatoidarthritis, failed back, end-stage cancer (i.e., breakthrough pain), etc.Post-operatively, for example, patients suffer from severe pain for thefirst few days followed by days of mild to moderate levels of pain.

The most common analgesic used to treat moderate to severepost-operative pain is IV morphine. This is either delivered on an “asneeded” basis by a nurse to the patient by an IV injection or commonly amorphine syringe is placed in a PCA pump and the patientself-administers the opioid by pressing a button which has a lock-outfeature. Other opioids, such as hydromorphone and fentanyl may also beused in this manner.

Treatment of acute pain is also necessary for patients in an outpatientsetting. For example, many patients suffer from chronic pain and requirethe use of opioids on a weekly or daily basis to treat their pain. Whilethey may have a long-acting oral or transdermal opioid preparations totreat their chronic underlying pain levels, they often need short-actingpotent opioids to treat their severe breakthrough pain levels.

Treatment of acute pain is also necessary “in the field” under highlysub-optimal conditions. Paramedics or military medics often are requiredto treat severe acute pain in un-sterile situations, where needles usedfor IV or IM administration can result in unintended needle sticks, riskof infection, etc. Oral opioid tablets often take 60 minutes to providerelief which is too long for someone in severe pain.

In a number of clinical settings, there is clearly a need for improvedmeans to administer a drug that produces effective pain relief in amanner that is titratable, safe and convenient, and non-invasive thatprovides relief from acute, severe breakthrough or intermittent painover an appropriate period of time.

The claimed methods and systems rely on administration of dosage formscomprising a pharmaceutically active substance such as sufentanil whichis effective for the treatment of pain (acute, intermittent orbreakthrough pain) using a dispensing device that includes features suchas lock-out, a means for patient identification prior to drugadministration and a means to protect the dosage forms stored therein.The claimed methods and systems thereby provide significant advantagesover currently available treatment modalities in terms of both safetyand efficacy.

Oral Transmucosal Administration

In practicing the invention, dosage forms are administered to the oralmucosa of a subject with or without a device, for example using a singleor multiple dose applicator.

In one exemplary embodiment, a dispensing device of the invention isused for oral transmucosal administration of a dosage form directly tothe patient in the inpatient (hospital, clinic, etc.) or outpatientsetting.

In other exemplary embodiments, a dosage is administered to the patientin the inpatient (hospital, clinic, etc.) or outpatient setting using adisposable single or multiple dose applicator.

Outpatient Acute Setting

One exemplary use of a dispensing device is to provide a rapid-actingdosage form that produces a therapeutic effect rapidly, may be usedsafely and conveniently, and provides a therapeutic effect for anappropriate period of time. The dispensing device of the invention maybe used in the outpatient setting. In the outpatient setting, oneembodiment of the dispensing device of the invention may exhibit thefollowing structural and functional features: the dispensing device maybe a standalone portable model; the dispensing device may be capable ofup to several weeks of treatment; the dispensing device may bedisposable, and/or non-refillable; the dispensing device may be childproof; the dispensing device may have a fixed lockout between doses; thedispensing device may exhibit a shutdown after a fixed period of time;the dispensing device may have an interface limited to a dispensebutton, sounds or tones, and LEDs; the dispensing device may monitor thetemperature and shutdown if the drug dosage exceeds safe limits; adisplay; and the dispensing device may have a dose counter.

When used in the outpatient acute (home, office, field, etc.) setting,the dispensing device of the invention offers several features andadvantages over the state of the art in outpatient drug administration.The dispensing device allows individuals to self administer drugs inaccordance with physician, healthcare provider, or drug labelguidelines. Some exemplary acute outpatient indications arepost-operative pain, pain associated with physical trauma, anxiety,insomnia, hypertension, angina, coronary artery disease, depression,psychosis, constipation, nausea, addiction, ADHD, and others. See, e.g.,U.S. application Ser. No. 11/429,904, expressly incorporated byreference herein. To effectively assist in the dispensing of drugs inthe acute outpatient setting, the dispensing device may provide some orall of the following features: allow the patient to self administer themedication; record a dosing history; allow the dosing history to be reador transferred to a computer, network or other electronic device; detertampering or diversion; deliver the drug dosage form to the appropriatelocation (e.g. sublingual, buccal, oral gastro-intestinal, rectal,ocular, nasal, inhalation, aural, transdermal or any other route ofadministration); and notify a pre-determined individual or individuals(by alert, alarm, cell phone message, text message, email, or otherwired or wireless communication means) of an event like a dosingadministration, a need for a refill of a prescription, a tamper attempt,a misuse of the device, a GPS location, an expiration of the drugcontained in the device, a temperature or humidity event. The dispensingdevice of the invention may be used to dispense any medication in theoutpatient acute setting, in any drug dosage form, affording anycombination of the features set forth above. Some examples of uses for adevice of the invention are in acute field care for first responders,military field medics, emergency rescue, etc.

For example, treatment of acute pain is often necessary “in the field”under highly sub-optimal conditions. First responders, such asparamedics or military field medics, often are required to treat severeacute pain in non-sterile situations, where needles used for IV or IMadministration can result in unintended risk, such as infection, and soon. The dispensing devices, systems and methods of the present inventionfind utility in this setting as well as in circumstances such as when asubject is suffering from angina, which may be treated withnitroglycerine using a dispensing device of the invention.

Chronic Outpatient Setting

Yet another embodiment of a dispensing device of the invention is in theoutpatient setting where chronic administration is needed for patientssuffering from chronic conditions.

One embodiment of the dispensing device for delivering drug dosage formsin dispensing device may be capable of 1-2 years of treatment; thedispensing device may be rechargeable and may be part of a system whichincludes a recharging station/dock/portable docking fob; the dispensingdevice may have a graphic display and indicator lights on the dispensingdevice; the dispensing device may be part of a system which includes adock, or fob; the dispensing device may include a keypad on the device;the dispensing device may include a dock, or fob; the dispensing devicemay record a dosing history; the dispensing device may allow the dosinghistory to be queried; the device may store one or more patient or useridentifications; the dispensing device is typically theft deterrent,child proof and has controlled access, the dispensing device may have aresetable counter; the dispensing device may have fixed or variablelockout times; the dispensing device may be refillable; the dispensingdevice may be networked; and the dispensing device may have an alertfunction.

When used in the outpatient chronic (home, office, field, etc.) setting,the dispensing device offers several features and advantages over thestate of the art in outpatient drug administration. The dispensingdevice allows individuals to self administer drugs in accordance withphysician, healthcare professional, or drug label guidelines. Examplesof chronic outpatient indications where a dispensing device of theinvention finds utility include chronic pain, chronic breakthrough pain,anxiety, insomnia, hypertension, coronary artery disease, depression,psychosis, addiction, ADHD, high blood pressure, diabetes, and others.To effectively assist in the dispensing of drugs in the chronicoutpatient setting the dispensing device may provide some or all of thefollowing features: the dispensing device may allow the patient to selfadminister the medication; record a patients' dosing history; allow thedosing history to be read or transferred to a computer network or otherelectronic device; allow a physician or healthcare provider to modifythe settings and programming either in person or remotely; automaticallyupload or transfer information at a pre-determined time, on apre-determined schedule or upon a specific event taking place; detertampering or diversion; deliver the drug dosage form to the appropriatelocation (e.g. sublingual, buccal, oral gastro-intestinal, rectal,ocular, nasal, inhalation, aural, transdermal or by any other route ofadministration); and notify a pre-determined individual or individuals(by alert, alarm, cell phone message, text message, email, or otherwired or wireless communication means) of an event like a dosingadministration, a need for a refill of a prescription, a tamper attempt,a misuse of the device, a GPS location, an expiration of the drugcontained in the device, a temperature or humidity event. A dispensingdevice of the invention may be used to dispense any medication in theoutpatient setting, in any drug dosage form, affording any combinationof the features set forth above.

In some embodiments, the dispensing device includes a docking connectoror wireless docking means and is capable of communicating with a systemwhich includes software and access to a computer network. A systemcomprising this device has a stationary or portable docking stationwhich bidirectionally transmits information from the device to a networkby wired or wireless mode or the hook-up may be by way of a dockingconnector or a wireless docking means, together with a means ofconnecting to a phone line, a computer, or a network.

In one exemplary embodiment the dispensing device would have twointerface modes: a patient mode and a medical personnel mode, e.g., anurse mode. In a patient mode, only the dispensing button would work,and the display and keypad would be non-functional. In the medicalpersonnel mode, the display and keypad would be functional and a nursewould be able to access the dosing history, the dosage strength, thepatient ID, the remaining doses in the device, and any other informationthat the dispensing device would have for nurse access. A nurse may havean RFID tag that the dispensing device would recognize as a medicalpersonnel access tag, shifting to the medical personnel interface modewhen it is present and switching back to the patient interface mode whenit is not present.

In another exemplary embodiment, the dispensing device of the inventionis used for administration of a sublingual tablet in the outpatient(home, office, etc.) setting. The dispensing device includes amicroprocessor, a memory means, a dispensing button for dispensing asublingual tablet, a small electronic speaker, and a docking connectoror wireless docking means. Additionally there would be a stationarydocking station that would contain a microprocessor, a memory means, adocking connector or a wireless docking means, and means of connectingto a phone line, a computer, or a network. In the patient dosing mode,the patient would depress the dispensing button when a dose wasrequired. If the patient presses the dispensing button during the timedlockout period between doses, a tone would sound, informing the patientthat he must wait before re-dosing and the dispensing device would notdispense a tablet. If the patient presses the dispensing button afterthe timed lockout period between dosing has expired, then the dispensingdevice would dispense a tablet and a confirmatory tone would sound,informing the patient that a dose had been dispensed. When thedispensing device is docked, either physically or wirelessly, to thestationary dock, the dispensing device would communicate with thepatient's physician by means of a dock or other communication means tothe physician's computer or other device, and exchange information,allowing the physician to view the patient's history, downloadinformation, reset a counter on the dispensing device, or enable ordisable any other features on the device in a remote fashion. When thedispensing device is removed from the dock, the dispensing device wouldreturn to the patient interface mode, unless the physician hadinstructed the dispensing device to do otherwise.

In yet another embodiment of the invention, a dispensing device of theinvention comprises some or all of the following features: the devicehas a patient identification feature, e.g., RFID; the device may monitorthe temperature and shutdown if the drug dosage exceeds safe limits; thedevice has a display; the device has a means for connection andcommunication with a docking station or other docking or communicationmeans such that the device is capable of connectivity for two-way datatransfer, e.g., automatic data upload and down load via a local orremote computer system.

To effectively assist in the dispensing of drugs in the acute outpatientsetting, the dispensing device may provide some or all of the followingfeatures: allow the patient to self administer the medication; record adosing history; allow the dosing history to be read or transferred to acomputer, network or other electronic device; deter tampering ordiversion; deliver the drug dosage form to the appropriate location(e.g. sublingual, or buccal); record a dosing administration or atemperature or humidity event.

When used in the outpatient acute (home, office, field, etc.) setting,the dispensing device of the invention offers several features andadvantages over the state of the art in outpatient drug administration.The dispensing device allows individuals to self administer drugs inaccordance with physician, healthcare provider, or drug labelguidelines. Some exemplary acute outpatient indications arepost-operative pain, pain associated with physical trauma, anxiety,insomnia, hypertension, angina, coronary artery disease, depression,psychosis, constipation, nausea, addiction, ADHD, vertigo and others.See, e.g., U.S. application Ser. No. 11/429,904, expressly incorporatedby reference herein.

The dispensing device of the invention may be used to dispense anymedication in the outpatient acute setting, in any drug dosage form,affording any combination of the features set forth above. Some examplesof uses for a device of the invention are in acute field care for firstresponders, military field medics, emergency rescue, etc.

Inpatient Setting

Another use for the dispensing device of the invention arises in theinpatient setting. For example, the need for rapid treatment of acutepain occurs in many different clinical situations, includingpost-operative recuperation, rheumatoid arthritis, failed back,end-stage cancer, etc. in the hospital settings. Post-operatively, forexample, patients suffer from severe pain for the first few daysfollowed by days of mild to moderate levels of pain.

In another embodiment the drug dispensing device is comprised of adisposable drug cartridge, a disposable dispensing end, a reusablecontroller end, a patient identification means like an RFID tag, aportable docking fob for controlling and accessing the drug dispensingdevice, and a base station for recharging the reusable dispensing endand the portable docking fob. In this embodiment the drug cartridge isloaded into the disposable dispensing end, which, in turn, is connectedto the reusable controller end and affixed together. This assemblycompletes the drug dispensing device which is capable of dispensingdosage forms to the patient upon request, providing a lockout periodbetween dosing, recording dosing and usage history, and allowing thishistory and the drug dispensing device settings to be reviewed orelectronically downloaded. An RFID tag would be affixed to a patient soas to provide a wireless identification means that would enable the drugdispensing device to operate properly when in proximity to the correctRFID tag. A healthcare provider could use the portable docking fob todock with the drug dispensing device, allowing access to settings,controls, history, and other features. When not in use, the reusablecontroller end and the portable docking fob could be placed in the basestation to recharge the batteries or power supply.

When used in the inpatient (hospital, clinic, etc.) setting, adispensing device of the invention offers several features andadvantages over the state of the art in patient drug administration. Thedispensing device allows healthcare providers to provide drug dosageforms to a patient for self administration of PRN (“Pro Re Nata”)medications. PRN refers to drugs that are taken as needed, such as forpain, nausea, constipation, anxiety, etc. To effectively operate in theinpatient setting, a PRN patient controlled dispensing device shouldallow the patient to self dose as needed, prevent the patient from overdosing, record the dosing history, allow for the dosing history to beread, downloaded, or otherwise transferred to a patient's records,deliver the drug dosage form to the appropriate location (e.g.sublingual, buccal, oral gastrointestinal, rectal, ocular, nasal,pulmonary, vaginal, aural, transdermal or any other route ofadministration) and prevent or deter unauthorized individuals fromgaining access to the drugs. The dispensing device of the invention maybe used to dispense any PRN medication in any drug dosage form in theinpatient setting affording any combination of the features set forthabove, as described in U.S. application Ser. No. 11/473,551, which isexpressly incorporated by reference herein.

A system comprising the dispensing device of the invention may have aportable dock which bidirectionally transmits information from thedevice to a network in a wired or wireless mode. Software fordownloading or uploading data, such as dosing histories, to a computersystem is also part of this embodiment of the invention.

In other embodiments, the dispensing device can be adapted to attach toa cord so as to allow the device to hang from the neck of the patient orto be affixed to the hospital bed, for example. This would help avoidmisplacing the device or theft of the device, such as in the hospitalsetting. The dispensing device may also have a clip so that it can beattached to an article of clothing or to a hospital bed.

The dispensing device may employ one or more theft deterrent features toprevent or deter unauthorized theft of, or tampering with the device orthe drug dosage forms therein. Such deterrents may be employed toprevent theft of, or tampering with the device within the hospital,clinic, or healthcare setting, within the home, office, or any otherlocation where the device is intended or not intended to reside orfunction, whether temporarily or permanently. Exemplary deterrentsinclude physical locks, tethers, cables, clamps, or other physicalattachments, whether permanent or temporary, to another object or to aperson.

An exemplary embodiment of a physical theft deterrent means is aflexible cable that locks to the dispensing device on one end and locks,by means of a loop, locking mechanism, or other attachment, to ahospital bed on the other end. In this embodiment the cable tether maybe unlocked from either the drug dispensing device or from the hospitalbed to enable patient ambulation or to enable disposal or reuse of thedevice by means of a key, combination, or other locking mechanism thataffords controlled access.

The deterrent means may include alarms or notifications that may triggeran alert on the dispensing device, on a dock or other peripheral device;on a computer or by means of a wired or wireless network, or may alertother remote devices. The alarm or notification may be audible, tactile,visual, or may employ other means of notifying one or more individuals.In one embodiment such an alarm or notification may indicate that thedispensing device has been stolen or is in the process of being stolen.In addition to an alarm, information about the theft event may betransferred to or from the device, including the time, date, audio data,visual data, GPS or other location information, or any other informationthat aids in the prevention of or tampering with the dispensing deviceor tablets therein. Such deterrents may involve an activation of afeature of the dispensing device, including a loud siren alarm, anelectric shock, a shutting down or destruction of one or more aspects ofthe device, the dispensing of an ink or other marker, or an action thatrenders the internal drug unusable or undesirable. The dispensing deviceof this invention may use one or more means to deter theft or tampering.

In some embodiments, One exemplary embodiment of such a deterrent meanscan be exemplified by the case of the delivery of a sublingual opiatetablet in the inpatient (e.g. hospital or clinic, etc.) setting. In sucha case the dispensing device includes a wireless proximity detection,like RFID or a detector for a wireless network, to detect when thedispensing device is removed from a predetermined proximity to a person,object, or physical location. Upon detecting that the dispensing devicehas been removed from a predetermined location or proximity, thedispensing device would shut down normal functionality, sound an audiblealarm, send a wireless alert message to a remote device or network, andtrigger the internal release of a liquid into the tablet cartridge insuch a manner as to wet and/or inactivate all tablets, rendering themunusable.

In another exemplary embodiment, the dispensing device of the inventionis used for delivery of a sublingual opiate dosage from in theoutpatient (e.g. home, office, etc.) setting, an internal sensor orswitch would detect when the dispensing device was opened, disassembled,damaged or lost power in an unauthorized or unintended fashion. Thedetection of this event would cause the internal micro processor to logan event record, if the system were able to, and trigger the internalrelease of a liquid opiate antagonist, like naloxone, into the tabletcartridge in such a manner as to wet all tablets, rendering themunusable as a opiate drug and unusable as a sublingual tablet dosagefrom.

The dispensing device may employ one or more levels of interface fordifferent types of authorized users, for example the patient, the nurse,the physician, pharmacist or other authorized medical or healthcarepersonnel. These different interfaces may include components such askeypads, buttons, graphical icons and instructions, lights, LED's,monochrome or color graphical or text displays, touch-screens, LCD's,sounds, tactile feedback, voice recognition interfaces, and other inputand output devices and means. The activity, or mode, of the userinterface may be determined by the mode of operation of the dispensingdevice, by a login or access activity by a user such as a password orcode entry, by the connection or disconnection of the dispensing devicefrom a dock, computer, or network, or by the detection of an authorizedaccess key, such as a key, and/or RFID tag, or similar combination. Uponchanging the interface mode, the functionality of the device may bechanged, either activating, inactivating or changing the functionalityof the various interface components described above. By allowing thedevice to have one or more interface modes, with differing functionalityassociated with each one, the device can be optimized for various uses.

In one exemplary embodiment, a dispensing device of the invention isused for administration of a sublingual tablet in the inpatient(hospital, clinic, etc.) setting. Such a device would contain amicroprocessor, a memory means, an LCD text and graphical display, akeypad with several buttons for navigating a graphical menu andselecting functions, and a dispensing mechanism for dispensing asublingual tablet.

The dispensing device can include a microprocessor, a memory means, amulti-color LED light, a dispensing button for dispensing a sublingualtablet, and a docking connector or wireless docking means. Additionally,there would be a portable handheld dock that contains a microprocessor,a memory means, a graphical and text display, a keypad, and a dockingconnector or a wireless docking means. When this dispensing device isused in the patient mode, the LED would display a one color, e.g.,green, when patient dosing was allowed, and it would display anothercolor, e.g., an amber color when patient dosing was not allowed becausethe dispensing device was in a timed lockout period, and the dispensingdevice would display a third color, e.g., a red color when thedispensing device malfunctioned. The patient would be able to selfadminister a sublingual tablet when the LED was green. In one scenario,a nurse or other authorized medical personnel would bring a portabledock into the patient's room and physically or wirelessly dock to thedispensing device, allowing the medical personnel interface mode to beoperable. In the medical personnel interface mode, a nurse would be ableto view the patient dosing history, the dosage strength, the patient ID,the remaining doses in the device, and any other information that thedevice would have for the nurse to access. Furthermore, a nurse couldreset dosing counters on the device, query error conditions, deliverbolus doses if needed, etc. When the portable dock was disconnected fromthe dispensing device, the dispensing device would return to the patientinterface mode.

VII. Dispensing Devices

Dispensing devices and systems for oral transmucosal administration ofsmall volume drug dosage forms are provided. The dispensing devices arehandheld and portable and comprise a housing having a dispensing endwhich typically has a proboscis with a shroud that provide a means forblocking or retarding saliva ingress and/or moisture control. Thedispensing devices further provide safety features such as a means forlock-out and a means for patient identification.

Single and Multiple Dose Applicators

The invention provides disposable applicators for delivering dosageforms to the oral mucosa such that application to a pre-determinedlocation for drug delivery (e.g. the mouth, sublingual space, etc.) iseffected.

In one approach to the invention, a dosage form, for example, a NanoTab™may be delivered to the oral mucosa, using a single dose applicator. Thedosage form is provided in a child-resistant drug dispensing device orpackaging and delivered to the oral mucosa, for example, the sublingualcavity, with supervision/assistance. Alternatively, the dosage form isadministered with supervision/assistance with or without a device.

In one embodiment, the invention provides dispensing device which canprovide for a pre-determined delay between doses in a liquid or geldispensing device. The mechanism includes a liquid or gel reservoir thatis slightly pressurized, for example by a propellant or a spring loadedplunger, a thin exit tube leading from the reservoir to a secondcylinder chamber. The cylinder chamber may contain a dispensing pistonattached to a rod, and a dispensing port that is much larger than thethin exit tube connecting to the reservoir. The dispensing port mayinclude a valve to prevent unintended dispensing of the drug. Theviscosity of the drug formulation, the pressure in the reservoir, andsize of the thin exit tube may be designed such that the viscous drugformulation slowly flows from the pressurized reservoir to the cylinderchamber, driving the piston backward until the chamber is full. Thisprocess takes a period of time that may be pre-determined andcoordinated with an appropriate lockout time between drug doses. Whenthe cylinder chamber is full, the dispensing valve may prevent drug fromescaping. To dispense drug from the cylinder, the rod is pressed. Theactuation of the rod also opens the dispensing valve allowing the liquidor gel to be dispensed. In one approach, the dispensing port is muchlarger than the exit tube, such that the drug is preferentially drivenout the dispensing port. Also, it is possible to dispense a drug usingthis system prior to the cylinder chamber being completely full. If thechamber fills at a constant rate, the amount of drug dispensed isproportional to the time that the chamber has been filled, up to thepoint that the chamber is completely filled. For this reason, if thedispensing device is actuated prematurely, the dispensing device willonly dispense a partial bolus of liquid or gel.

In one embodiment, a single dose applicator (SDA) is used to administervariety of drug dosage forms, including a solid tablet, a liquidcapsule, a gel capsule, a liquid, a gel, a powder, a film, a strip, aribbon, a spray, a mist, a patch, or any other suitable drug dosageform.

The single dose applicator (SDA) may contain the dosage form within, mayhave the drug dosage form attached or affixed to it, may have the dosageform dissolved in it, and may afford a seal against moisture, humidity,and light. The single dose applicator may be manually manipulated by apatient, healthcare provider, or other user to place the dosage form inthe proper location for drug delivery.

In practicing the invention, a single- or multiple-dose applicator ordrug dispensing device may be used to deliver tablets or other dosageforms into the hand, the mouth, under the tongue, or to other locationsappropriate for specific drug delivery needs.

In one embodiment, a single- or multiple-dose applicator or drugdispensing device is used to deliver a dosage form to the oral mucosa,e.g., the sublingual space.

The dosage forms inside the dispensing device remain dry prior todispensing, at which point a single dosage form is dispensed from thedevice into the mouth, e.g., the sublingual space, wherein a patient'ssaliva will wet the tablet and allow for tablet disintegration/erosionand drug dissolution.

The SDA may be provided as a pair of forceps, a syringe, a stick or rod,a straw, a pad, a dropper, a sprayer or atomizer, or any other formsuitable for the application of a single drug dosage form. After use,the SDA may be disposed of, so as to eliminate the risk of contaminatingthe drug dispensing device with saliva, or other contaminants.

In one aspect of the invention, a small volume dosage form according tothe present invention is placed in the sublingual cavity, preferablyunder the tongue on either side of the frenulum linguae, such that itadheres upon contact.

For sublingual administration, a small volume dosage form may beadministered sublingually by placement under the tongue, adjacent to thefrenulum using forceps. Alternatively, a small volume dosage form may beadministered sublingually by placement under the tongue, adjacent to thefrenulum using a syringe, a stick or rod, a straw, a dropper, or anyother form suitable for the application of a single drug dosage form,including but not limited to a SDA, as further described herein.

The dosage forms may be provided in a package that consists of moldedplastic or laminate that has indentations (“blisters”) into which adosage form, is placed, referred to herein as a “blister pack”. A cover,typically a laminated material or foil, is used to seal to the moldedpart. A blister pack may or may not have pre-formed or molded parts.

In one embodiment, the blister pack has two flexible layers that aresealed with the dosage form in between and the primary unit dose blisterpack also serves as an applicator for delivering a single dosage form tothe sublingual space, once the child-resistant foil is peeled back.

In yet another embodiment of the invention, a long tape or array ofdosage forms sealed between a flexible blister layer and a foil orotherwise breakable layer is provided. A push rod is positioned above adosage form, and upon actuation pushes against the blister, forcing thedosage form through the foil or breakable layer, dispensing the dosageform.

Such blister packs may be provided in a child resistant multiple dosagedrug dispensing device.

The claimed dispensing devices, methods and systems comprise delivery ofsmall volume dosage forms to the oral mucosa. The invention is notlimited to the specific devices, systems, methodology and dosage formsdetailed herein, as these may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention.

There is a continuing, unfilled need for a drug dispensing device thatcan accurately dispense a given medication to the correct patient in amanner that is cost-effective, minimizes the risk of error, is resistantto accidental and intentional abuse and diversion, eliminates the needto handle the medication and is not labor-intensive.

In another embodiment, the present invention provides a drug dispensingdevice that greatly simplifies the logistics of dispensing single andmultiple doses of a given medication under controlled conditions. Oneexemplary use of a drug dispensing device of the invention is in theadministration of controlled substances such as opioids. In such cases,the dosage form contains a highly potent and controlled narcotic drugthat must be contained and administered under controlled conditions.Storage and delivery of such a formulation requires a specially designeddevice. The device must safely store the dosage form, prevent or deterabuse or accidental or inadvertent misuse, readily and accurately allowdispensing of individual dosages only to the patient for whom the drugwas prescribed in an efficacious and safe manner as well as provide ameans for monitoring and reporting of the history of use. The drugdispensing devices of the present invention meets these needs.

In another embodiment, the dispensing device comprises a package thatholds a single or multiple drug dosage forms, a distal orifice fordelivery of the drug dosage form, an internal mechanism that segregatesand releases the dosage forms, internal electronics that control thenumber of dosage forms that can be delivered in a given time period(lockout time), a security feature that limits access to the device tothe patient and/or one or more healthcare professionals, a securityfeature that reduces likelihood of dispensing device theft, a queriableinterface that allows for dispensing device use history information tobe stored and retrieved, a means of preventing saliva from penetratingthe device, and an external switch for the user to actuate thedispensing device. The dispensing device is typically handheld and maybe capable of data communication by way of a docking station (“dock”). Afixed or portable dock may be incorporated to aid in charging thedispensing device and for data access by authorized healthcareprofessionals. The dispensing device is capable of shutting down if auser does not match patient ID, lockout period has not expired when adosing attempt is made, or sensors indicate that the drug form is nolonger good (due to humidity, heat or expiration). The dispensing deviceis capable of issuing alarms when functional issues arise. In one aspectof this embodiment, the drug dosage form and drug dispensing device aredesigned for oral transmucosal drug delivery, e.g., into the sublingualspace.

In another embodiment, the dispensing device of the invention includes adetecting means for patient identification such as a fingerprint reader,an optical retinal reader, a voice recognition system, a facerecognition system, a dental imprint recognition system, a visualrecognition system, or a DNA reader. The dispensing device may employone or more means to identify the user, enabling the system to determineif a dispensing request is being made in an authorized or unauthorizedmanner. It is important for effective delivery of many potential drugsand drug dosage forms to ensure that the dispensing device is notaccidentally or intentionally used by an unauthorized individual toprevent accidental or intentional diversion of the drug. Such patientidentification systems may recognize one or more users, for example, inan inpatient hospital setting the dispensing device could be programmedto recognize the patient to whom it is prescribed, as well as authorizedhealthcare providers such as nurses and physicians. In an outpatienthome setting, for example, the dispensing device may only respond to thepatient to whom it is prescribed. The dispensing device may employ anymeans of user identification, including fingerprint identification, RFIDdetection with the use of an active or passive RFID tag on bracelet,necklace, clip, belt, strap, adhesive patch, implant, or means oflocating and affixing a tag, retina identification, DNA identification,voice recognition, password or code entry, physical key, electronic ormagnetic key, personal area network identification using the human bodyor clothing as a data or signal conduit, optical scanner or facerecognition, sonic, subsonic or ultrasonic identification, or any othermeans of identifying an individual and verifying their identity.

One method of patient identification is the use of a short distance(“near field”) passive RFID tag attached to a bracelet, necklace,adhesive patch, clothing tag, orally mounted device, like an orthodonticretainer, belt, strap, some combination of these, or another location.When an RFID tag is used in the “near field”, roughly defined as about16% of the wavelength of the received signal, the tag behaves in theinductive mode of operation, coupling between the reader and tag antennamagnetically. The near field is characterized by at least two features:first is a rapid decline in field strength with distance, and second isa strong directionality of the signal. In the near field, the signalstrength falls off very rapidly, with a signal strength loss ofapproximately 60 dB per decade in distance. For good inductive couplingbetween the transmitter antenna and the RFID tag antenna, the twoantennas are oriented in parallel planes with the axes through thecenter of each antenna in close proximity. Strong signal strength(robust patient identification) is provided when the device is veryclose to the RFID tag. At the same time, a very poor signal is providedwhen the device is further away from the tag, which helps preventunauthorized use by someone other than the patient who attempts to usethe device. It is preferable to operate in this near field region withgood antenna alignment. Furthermore, it is preferable to operate with avery short distance of adequate signal strength for a positiveidentification, so that it is very difficult to receive a signal if thedevice is not in the proper orientation and proximity to the RFID tag.To attain a short distance and a proper alignment between antennas, thedispensing device may be designed so as to properly locate the RFIDreader antenna, mounted in the dispensing device, adjacent to an RFIDtag antenna, mounted, for example, on a wrist band or bracelet, or aclothing tag on the collar, or an adhesive patch on the hand, arm,cheek, neck, or elsewhere. Furthermore, an RFID tag antenna on a wristband or bracelet may be held in proper alignment and location by meansof a small adhesive patch that prevents the bracelet from moving orrotation on the wrist.

In another embodiment, the dispensing device employs a high frequencyRFID reader for use in the inpatient (hospital, clinic, etc.) setting,operating on or near the 13.56 MHz frequency band, and the patient is befitted with a matching RFID tag and antenna on a disposable bracelet orwrist band, designed in such a way that if the bracelet or wrist band isremoved the RFID tag, the antenna, or another component of theassociated circuit will be damaged or destroyed, rendering the braceletor wrist band non-functional. In one example, the range of the RFIDcommunication is short, between 0 inches and 10 inches preferably, morepreferably between 0 and 5 inches, and most preferably between 0 and 3inches, and may additionally be directional, allowing proper use by theintended patient to be easy and reliable, while at the same time makingunauthorized use by another individual difficult, very difficult, orimpossible.

In another embodiment, the dispensing device of the invention for use inthe outpatient setting (e.g. home, office, etc.) would include anelectronic fingerprint sensor system and would be trained to identifythe patient's fingerprint at the time of prescription or first use. Whenthe intended patient doses herself, she would first use the fingerprintidentification sensor to attempt identification. Once the dispensingdevice has successfully identified the patient as the authorized user ofthe device, the dispensing device would allow a single dosing,effectively unlocking itself for a brief period of time, for example 5seconds. Once the dose has been delivered or the 5 seconds have elapsedthe dispensing device would effectively re-lock itself, requiringanother fingerprint identification prior to another dosing.

In another embodiment, the dispensing device of the invention allows fora heart rate measurement, and does not dispense a dose unless thepatient's heart rate is within a pre-specified range. The dispensingdevice may have any of a number of a number of types of sensors formeasurement of internal and external parameters including biometricparameters such as body temperature, respiratory rate, blood pressure,blood chemistry, saliva chemistry, breath chemistry, or any otherbiological state or detectable input, or include external parameterssuch as time, date, temperature, humidity, global position, etc.

In another embodiment, the dispensing device of the invention may have adose counting feature that monitors and stores the history of drugusage, including a global dosing counter that counts all doses takensince the device was set up, and a resettable dosing counter that may bereset by authorized medical personnel, e.g., a nurse and tracks dosestaken since the last reset. The dispensing device of the invention cancount and display the number of doses which have been dispensed and thenumber of doses that are remaining to be dispensed.

In addition, in another embodiment, the dispensing device of theinvention may have a memory means for retaining information about thedose delivered over time. The memory means may include RAM and/or ROM. Acentral processing unit (CPU) for processing information and controllingvarious functional elements of the device is also provided.

In another embodiment, the dispensing device of the invention may alsohave a convenience feature that can provide for ease of use. Exemplaryconvenience features include disposability, reusability, ease of refill,remote wired or wireless activation, rechargeable batteries, andmultiple dose capability.

In another embodiment, the dispensing device of the invention may alsohave a drug expiration alert feature that can prevent inappropriatedosing of an expired drug; drug expiration information; an interface forexchanging information with another device such as a computer; a clockfeature to track date and time for drug access control; and/or othercommunication capabilities that may be time dependent.

In another embodiment, the dispensing device of the present inventionprovides a drug delivery device that is capable of controlled deliverythat is electrically monitored and controlled such that the patientreceives a dose that is both safe and efficacious.

In another embodiment, the drug dispensing device of the presentinvention is an easily handled, portable, self powered, relativelyinexpensive device that allows for timed lock-out periods to avoidoverdosing, is child-proof and tamper proof, and is capable ofmulti-unit dosing, such that days, weeks or months of medication can behoused in the device.

In another embodiment, the drug dispensing device of the presentinvention may include the following structural components which arefunctionally connected: a drug reservoir, a dispensing tip, a manual orpowered activation trigger or button, one or more communication port(s),an internal power supply, a user interface with input and outputfunctions, a microprocessor, wireless communication capability, patientand user identification (e.g. fingerprint reader, RFID) capability,saliva ingress prevention, internal humidity and moisture control, anopioid antagonist reservoir, a refilling or other access port, one ormore sensors to detect internal and external states, and biometric oraccess code input.

In another embodiment, the drug dispensing device of the invention mayemploy one or more sensors inside or outside of the dispensing device tomonitor various inputs. Some inputs may be indicators of internal systemstates, such as the number of tablets in the device, the location oftablets within the device, the successful dispensing of a tablet, anunsuccessful dispensing attempt, the presence of a tablet at a specificlocation, the presence of a tablet cartridge, the identity of thecartridge, the position of the dispensing mechanism, the temperature orhumidity within the device, or the sensing of any other internalconfiguration or state. Other inputs may be indicators of conditionsexternal to the device, including temperature, humidity, acceleration,light, or proximity to a user, another person, or an object, amongothers. These inputs may be specific to a user or other person and mayinclude direct or indirect interactions with the device, actuation oractivation of a switch, button, or other input, body temperature, heartrate, respiratory rate, blood pressure, blood chemistry, salivachemistry, breath chemistry, pupil dilation, or any other biologic stateor detectable input. The sensors may employ any means of detecting aninput. A range of sensors for detecting temperature, humidity,acceleration, saliva ingress, or other biometric input may serve as ameans to allow the device to activate or shut down under predeterminedor programmable conditions.

In another embodiment, the drug dispensing device may be powered by abattery, capacitor, fuel cell, or other power supply source, or mayrequire no electrical power, but be manually activated.

In some embodiments, the drug dispensing device of the inventionincludes a battery that can be charged by a photovoltaic cell ormanually by a hand-actuated crank or lever. A rechargeable battery orother power source may be recharged in a dock, with a recharging cable,or by other means.

Blocking/Retarding Saliva and Moisture Ingress

The claimed dispensing devices comprise a means for minimizing oreliminating saliva ingress and moisture ingress into the dispensingdevice: (1) to avoid wetting the dosage forms therein; (2) to isolateany saliva that enters the dispensing device in such a manner that thedosage forms therein remain dry; (3) to absorb or adsorb any saliva thatenters the dispensing device in such a manner that the dosage formsremain dry; (4) to block saliva and moisture from entering the device toprotect the dosage forms from vapor and liquid phase moisture, or (5)any combination thereof.

The dispensing device has a means for preventing and/or controllinghumidity ingress due to ambient conditions outside of the device.

The means for minimizing or eliminating saliva ingress or preventingother moisture from entering the dispensing device includes, but is notlimited to, one or more flexible or rigid seals, one or more flexible orrigid wipers, use of one or more absorbent material components such as adesiccant or pad, a door or latch that is manually or automaticallyopened and closed, multiple stage delivery systems, a positive airpressure and airflow, or an air gap or prescribed distance orbarrier/shroud maintained between the tablet delivery orifice and themucus membrane tissues within the mouth that may transport the saliva.The shroud limits the ability of the tongue or sublingual mucosa tocontact the dosage form dispensing area, thereby controlling salivacontact and ingress. By inhibiting or eliminating the “wetness” insidethe shroud and on the surface of the valve/seal, the dosage form isdispensed without adhesion occurring between the dosage form and theshroud or valve/seal. The drug dispensing devices of the inventionprovide a means for minimizing or eliminating saliva ingress into thedispensing device during administration of the drug to the oral mucosaof the patient.

To protect the drug dosage forms from exposure to moisture either fromhumidity, saliva ingress, or accidental exposure to other water basedliquids, the dispensing device and the container or cartridge whichhouses the dosage form within the device contains a desiccant.Mechanisms to prevent drug dosage forms inside a device of theinventions from exposure to moisture include but are not limited to useof desiccants, seals, absorbents, adsorbents, wipers, and sensors.

Means for trapping or otherwise isolating saliva or moisture if itenters the device include, but are not limited to, a hydrophilic wickingmaterial or component, an absorbent or adsorbent material or component,a desiccant material or component, a separate track or channel formoisture to collect, a separate channel to communicate moisture to theabsorbents or adsorbents, or any combination of these materials orcomponents.

A desiccant is a sorbant, in the form of a solid, liquid, or gel thathas an affinity for water, and absorbs or adsorbs moisture from it'ssurrounding, thus controlling the moisture in the immediate environment.Any commercial desiccant may be used. Commercial desiccants typicallytake the form of pellets, canisters, packets, capsules, powders, solidmaterials, papers, boards, tablets, adhesive patches, and films, and canbe formed for specific applications, including injection moldableplastics. There are many types of solid desiccants, including silica gel(sodium silicate, which is a solid, not a gel), alumino-silicate,activated alumina, zeolite, molecular sieves, montmorillonite clay,calcium oxide and calcium sulfate, or others, any of which may be usedin the claimed dispensing devices. Different desiccants have differentaffinities to moisture or other substances, as well as differentcapacities, and rates of absorption or adsorption. Also, different typesof desiccants will come to equilibrium at different relative humiditiesin their immediate surroundings. As a means for protecting the dosageforms and the internal portions of the dispensing device from moisture,one or more desiccants may be employed at the proboscis; in or adjacentto the dosage form; in or adjacent the delivery pathway; in or adjacentthe dosage form, tablet magazine or cartridge; in or adjacent to othercomponents of the dispensing device; formed as an injection moldedcomponent of the dispensing device; a compressed desiccant that ispressed into location; or desiccant in any other location within orwithout the device.

In one preferred embodiment, the desiccant snaps into a cavity in theside of the cartridge. There are holes in the desiccant cavity thatconnect it to the dosage form stack, exposing the dosage forms todesiccant and keeping them dry.

The claimed dispensing devices rely on valves, pads, seals, the restposition of the push rod, proboscis design and a shroud to minimize oreliminate saliva ingress or moisture into the dispensing device duringadministration of the dosage form.

Valves for use in the claimed devices are typically dome/trocar typevalves that provide enough sealing force to keep saliva and/or moisturefrom entering the device and serve to minimize or eliminate salivaingress or moisture by closing the distal orifice during dispensing andafter a dosage form has been dispensed.

Pads for use in the claimed devices have various geometries that aid incontacting or communicating with the pushrod in order to removed liquidfrom the push rod surface. Such pads typically contain hydrophilicproperties and serve to minimize or eliminate saliva ingress or moistureingress by transporting the liquid away from the track and push rod.

Seals and wipers for use in the claimed devices are designed to maintaina uniform seal around a drug dosage form and a pushrod during deliveryand are characterized by flexible materials that impart a seal aroundthe dosage form and pushrod and serve to minimize or eliminate salivaingress or moisture by sealing and wiping the orifice and pushrodbefore, during, and after dispensing.

The rest position of the push rod in the claimed devices ischaracterized by positioning the pushrod in an intermediate locationdistal to the cartridge exit, and proximal to the distal dispensingorifice and serves to minimize or eliminate saliva ingress and moistureby allowing the pushrod to reside in a location that contains adesiccant, absorbents, or channel that dries the pushrod while at restbetween dosage dispenses.

The proboscis design for use in the claimed devices is characterized bya distal device shape, typically an S-shape, that aids in use of thedevice and/or placement of the tip on the oral mucosa of the subject.The shape typically has curves, angles, and geometries such that itenables proper use of the device and placement of the dosage form on theoral mucosa of the subject, e.g., in the sublingual space.

The shroud of the claimed devices has a geometry that forms a barrierbetween the device and the oral mucosa and tongue, a relief for dosageform delivery, and an interior that is hydrophobic or hydrophilic andserves to minimize or eliminate saliva ingress or moisture ingress bycreating a barrier from the oral mucosa contacting the valve area anddosage form, aiding in dosage form dispensing and discouraging dosageform adherence to the shroud. The shroud may have a rounded interiorsurface or other geometries to mitigate the dosage form adhering to theshroud. The shroud limits the ability of the tongue or sublingual mucosato contact the dosage form dispensing area, thereby controlling salivacontact and ingress.

FIG. 1A is a schematic depiction of one embodiment of a dispensingdevice 10 for delivering drug dosage forms to a patient. The dispensingdevice 10 includes a graphic display 12, a biometric patientidentification reader 13, a user interface 14, a dispensing button 16,and a housing 18 in which a dispensing cartridge is located. Thedispensing device 10 is constructed to hold a plurality of dosage forms.The graphic display 12 includes an LCD display that enables thedispensing device 10, for instance, to monitor and display dosingfrequency, patient information, and/or schedule information. The userinterface 14 may used for navigating and selecting menu items displayedon the graphic display 12. The dispensing button 16 may dispense singledoses when pushed by a user, such as a patient. This allows postoperative or otherwise incapacitated patients to operate the devicewithout undue physical exertion. It also allows an attending nurse orphysician to dispense a dose to the patent and monitor their dosinghistory. The dispensing button 16 may either actively dispense a dosageform or trigger a logic switch that will inform a processor within thedevice that a dispense request has been made. The patient identificationreader 13 requires input of identification (e.g. fingerprint reader,optical retinal reader, voice recognition, dental recognition, facerecognition system, or DNA reader, RFID) or an access code to preventaccidental or intentional diversion or abuse from unauthorizedindividuals.

In one exemplary embodiment, the dispensing device 10 may employ a highfrequency RFID reader for use in the inpatient (hospital, clinic, etc.)setting, operating on or near the 13.56 MHz frequency band, wherein thepatient is fitted with a matching RFID tag and antenna on a disposablebracelet or wrist band, designed in such a way that once the bracelet orwrist band is removed the RFID tag, the antenna, or another component ofthe associated circuit is damaged or destroyed, rendering the braceletor wrist band non-functional. In one example, the range of the RFIDcommunication is short, between 0 inches and 5 inches, and mayadditionally be directional, allowing proper use by the intended patientto be easy and reliable, but at the same time making unauthorized use byanother individual difficult, very difficult, or impossible.

In another exemplary embodiment, the dispensing device 10 for use in theoutpatient setting (e.g. home, office, etc.), the biometric patientidentification reader 13 is an electronic fingerprint sensor system andwould be trained to identify the patients' fingerprint at the time ofprescription or first use. When the intended patient doses herself, shewould first use the fingerprint identification sensor to attemptidentification. Once the dispensing device 10 has successfullyidentified the patient, the patient identification reader 13 preventsthe possibility of accidentally or intentionally switching devices withanother patient and an accidental or inadvertent misuse of the device10.

FIG. 1B is a schematic depiction of the dispensing device 10 fordelivering drug dosage forms to a patient. In this embodiment, thedispensing device 10 includes a docking connector 20. The dockingconnector 20 can allow the dispensing device 10 to connect to anotherdevice, peripheral, or computer to retrieve, store, communicate data tothe other device, peripheral, or computer.

FIG. 1C is a schematic depiction of one embodiment of a dispensing tip22 of a dispensing device for delivering drug dosage forms to a patient.The dispensing tip includes a dispensing shuttle mechanism 24 near adispensing end 26.

FIG. 1D is a cross-sectional schematic depiction of another embodimentof the dispensing device 10 for delivering drug dosage forms to apatient. The dispensing device 10 includes a cartridge assembly 30; oneor more batteries 32; a processor and pc board 34; an antenna 36; and anantagonist reservoir 38. The dispensing device 10 may contain a shuttlemechanism, such as shuttle mechanism 24, to remove a drug dosage formfrom a stack and the dispensing end may have a slider mechanism todispense single doses when the dispensing button is pushed.

The dispensing device of the present invention may comprise one or moreof the following features: be hand held or portable; comprise a graphicdisplay, interface buttons, scroll buttons and a dispensing button;comprise a biometric finger print reader or other means to identify andconfirm that the correct patient is using the device; comprise an RFIDreader; comprise a dose counting feature; comprise a memory means forretaining information about dosing history; comprise an interface forbidirectional exchange of information with another device such as acomputer; comprise an LED, light, sound or tactile indicator that isactivated when a dosage form is dispensed; be capable of dispensing asingle dosage form at a time; not require the opening and closing of alid or other hinged aperture in order to dispense a dosage form;comprise an antagonist reservoir; comprise an indicator, wherein theindicator notifies a patient when it is time to take a dose or comprisean indicator, wherein the indicator provides notification in the eventof a potentially dangerous or non-efficacious dosing situation orcomprise an indicator, wherein the indicator notifies the patient of theremaining time to the end of the lockout period.

In some embodiments, the dispensing device of the invention has thevisual look of a pipette (as shown, for instance, in FIG. 1A) andtherefore is not enticing to a child (as opposed to the ACTIQ lozengewhich has the look of a lollipop).

In one exemplary embodiment, the dispensing device is a handheld device,with a control interface on one end and a dispensing device tip on theother. The control interface has a number of features, selected from anLCD monitor screen (for example, the graphic display 12 shown in FIG.1A), a speaker for user feedback, various interface and/or scrollbuttons (for example, the user interface 14 shown in FIG. 1A), adispensing button (for example, the dispensing button 16 shown in FIG.1A), and a biometric thumbprint reader (for example, the biometricpatient identification reader 13 shown in FIG. 1A). The dispensing endmay have a slider mechanism (for example, the user interface 14 shown inFIG. 1A) to dispense single doses when the dispensing button is pushed.

FIG. 2 is a schematic depiction of a cartridge assembly 40 for use in adispensing device for delivering drug dosage forms. The cartridgeassembly 40 includes a cap 42, a spring 44, a plunger 46, dosage forms48, and a cartridge tube 50. To assembly, the drug dosage forms 48 areloaded into the cartridge tube 50, followed by the plunger 46, thespring 44 and the cap 42. Once this cartridge is assembled it isinserted into a drug dispensing device, such as dispensing device 10.

FIGS. 3A-E provide schematic depictions of a variety of aspects of oneembodiment of a drug dispensing device constructed to hold a pluralityof dosage forms for oral transmucosal delivery. FIG. 3A is a schematicdepiction of a fully assembled or single piece dispensing device 5011 ofthe invention. In FIG. 3B, the dispensing device 5011 includes areusable head 5013 and a disposable body 5015; in FIG. 3C the dispensingdevice 5011 further includes a cartridge 5017 in FIG. 3D the dispensingdevice 5011 includes a valve 5033, a proboscis 5031, a latch button5019, a power train coupling 5025, a hub lock 5021 and a dispense button5023; and FIG. 3E is a schematic depiction of a reassembled and completedispensing device 5011.

FIG. 4 provides a schematic depiction of an exemplary dispensing devicewherein the dispensing tip includes a proboscis 5031 comprising a shroud5029 having a one or more of: a wiping/sealing valve 5033, 5035, anabsorbent pad 5039, a drug drying chamber/moisture communication channel5043, desiccant 5045 in the channel 5043, a cartridge 5017 containingdosage forms 5067 and desiccant 5047 in the cartridge 5017. A pushrod5051 is configured to push the dosage form 5067 through the channel5043.

FIGS. 5A and 5B are schematic depictions of an exemplary geometry forthe dispensing tip that prevents contact of one or more seals 5033, withthe moist or wet surface of the oral mucosa via a shroud 5029.

FIGS. 6A-D are a schematic depiction of an exemplary proboscis 5031 hasan S-shape 5053 of a dispensing device, for example the dispensingdevice 5011, as shown and described above with reference to FIGS. 3A-3D,wherein the proboscis 5031 comprises a shroud 5029, a valve 5033 fordispensing a dosage form and a cut-out/relief 5055 for the dosage formto be placed against the oral mucosa and not moved when the device 5011is withdrawn following dispensing.

FIGS. 7A and 7B are schematic depictions of a drug dosage form beingpushed through a seal by a pushrod, wherein the geometry of the seal istailored to the shape of the dosage form and pushrod. FIG. 7A depicts adispenser 254 comprising drug dosage forms 48, a cartridge 255, septumor seal 256, and a pushrod 257, wherein the drug dosage forms arestacked for dispensing. In the dispenser 254 in FIG. 7B 256, drug dosageforms 48 are being pushed through the septum 256 by the pushrod 257,wherein the geometry of the septum 256 is tailored to the shape of thedosage form 48 and the pushrod 257.

FIG. 8 is a schematic depiction of geometry 258 of an exemplary pushrod260, drug dosage forms 48, and septum-type seal 264. The exemplary slittype septum seal 264 is designed to maintain a uniform seal around thedrug dosage form 48 and the pushrod 260 during delivery. Additionally,the means for transporting the drug dosage forms through the seals,wipers, doors, absorbents, etc. may include the use of a push rod orshuttle that is specifically designed to limit saliva ingress andmanipulate the tablet through the components.

FIGS. 9A-9F are schematic depictions of the geometry 266, 268, 270, 272,274 and 276 respectively, of other exemplary slit type septum sealsdesigned to maintain a uniform seal around a drug dosage form and apushrod during delivery of the drug dosage form. The exemplary slit typeseptum seal is designed to maintain a uniform seal around a drug dosageform and a pushrod during delivery. Additionally, the means fortransporting the drug dosage forms through seals, wipers, doors,absorbents, etc. may include the use of a push rod or shuttle that isspecifically designed to limit saliva ingress and manipulate the tabletthrough the components.

A means for minimizing saliva ingress and moisture into the claimeddevices is important for preservation of the integrity of dosage formsduring storage, e.g., prior to and between oral transmucosaladministrations.

The claimed dispensing devices may be used to administer a drug dosageform that is sensitive to moisture and/or humidity. In such cases, adrug dosage form cartridge serves to protect the drug dosage form fromliquid and vapor phase moisture, including humidity, liquid moisture,saliva, mucus, etc. The cartridge may be cylindrical, disk-shaped,helical, rectilinear, non-ordered, or may take the form of anyassemblage of drug dosage forms that allows the drug dispensing deviceto dispense them in a controlled manner. To prevent the unused drugdosage forms from absorbing moisture or otherwise becoming exposed tomoisture prior to use, the cartridge may provide a means of sealing thedrug dosage forms from exposure to moisture. This may accomplished byuse of a cartridge that contains individually packaged drug dosage formsseparated by a thin impermeable foil or impermeable material such thatwhen one drug dosage form is dispensed from the cartridge, the sealprotecting the remaining dosage forms remains unbroken. Alternatively,the dosage forms may be packaged in such a manner within the cartridgethat two or more dosage forms are packaged together in each separatesealed compartment. In some embodiments, all of the dosage forms in acartridge may be packaged together in a foil sealed compartment.

A drug cartridge that houses small volume drug dosage forms within thedispensing device may afford a seal against moisture by means of aseptum, an elastomeric seal or valve, a sliding, translating, hingeddoor or valve, or by means of sealing against another component of thedrug dispensing device when loaded. In this manner, a single re-sealableseal may be opened either independently or by means of the passage of adosage out of the cartridge. Once the dosage form is delivered from thecartridge, the re-sealable seal on the cartridge may be re-sealed toprevent moisture or other contaminants from damaging the remaining drugdosage forms within the cartridge. The cartridge may further have anon-re-sealable seal that is broken when it is loaded into the drugdispensing device or upon delivery of the first dosage form from thecartridge.

In other embodiments, the cartridge contains a desiccant or otherabsorbent or adsorbent material to absorb or adsorb moisture thatpenetrates the cartridge either prior to use or during normal use. Acartridge for use in a claimed dispensing device may contain anycombination of individually sealed dosage forms, multiply sealed dosageforms, re-sealable seals, non-re-sealable seals, desiccants, absorbents,or adsorbents. In one embodiment, a cartridge for use in the dispensingdevice in holds sufficient drug dosage forms for 1-5 days of treatment,e.g. 40 dosage forms or sufficient drug dosage forms to provide 48 to 72hours of treatment.

Dispensing Mechanism

FIGS. 10A-10D are schematic depictions of an exemplary dispensing device58 for delivering drug dosage forms 48, wherein a means for minimizingsaliva influx into the dispensing device 58 during the administration ofthe dosage forms 48 to the patient is provided. The dispensing device 58includes a pusher/slider 60, a housing 62, a push rack 64, pinions 66,and a channel 68 in the housing and a spring 72. FIGS. 10A-10D depict amultiple stage dispensing of drug dosage forms 48 as a means to reducesaliva ingress into the dispensing device 58. In FIG. 10A, thepusher/slider 60 is ready to push rack 64 and pinions 66 housed in thehousing 62 of the device 58. The channel 68 provides space for thepusher 60 to freely move within the channel 68. The drug dosage form 48is sitting on top of the rack 64 and spring 72 provides necessarytension in moving and returning the rack 64 and mechanism. In thedispensing device 58 shown in FIG. 10B, the pusher/slider 60 is movingthe rack 64 and pinions 66 housed in the housing 62 of the device 58.The drug dosage form 48 is pushed upward within the channel 68 by theforce provided by the spring 72 on the rack 64. In the dispensing device58 shown in FIG. 10C, the dosage form 48 is being dispensed from the endof the channel 68 and into a subject, such as human. Then the steps arerepeated for successive dispensing of the dosage form 48 minimizingsaliva ingress into the device 58 as shown in FIG. 10D. Salivainflux/ingress into the dispensing device 58 may be minimized byinclusion of seals, wipers, absorbents, desiccants, ejection typedevices, air gaps, or combinations thereof, or any other means ofminimizing saliva ingress in the device design. A means of allowingsaliva to enter the device while preventing saliva from reaching theremaining tablets within the device may include one or more flexible orrigid internal wipers or seals, a drug dosage cartridge that contains aplurality of individually packaged or isolated drug dosage forms, adelivery pathway for the tablet from a drug dosage cartridge to the exitport that is tortuous or multi-staged in such a manner that saliva ormoisture not capable of wicking up the delivery pathway.

FIG. 11A is a schematic depiction of an exemplary dispensing mechanismfor a dispensing device 100 for delivering small-volume oraltransmucosal drug dosage forms, wherein a column type dispensingmechanism at a rest position. The dispensing mechanism includes one ormore cartridge assembly 102, an activation button 104, a motor 106, acam 108, desiccant 110, one or more seals 112, a delivery sensor 114, aspring clip 116, and a spring 118. The dispensing device 100 of theinvention provides for dispensing of dosage forms based on a stack orplurality of dosage forms 48 contained in the tubular cartridge ormagazine 102, with a spring 120 at one end wherein a loading force isapplied to the stack of dosage forms. FIG. 11B is a schematic depictionof the dispensing device of FIG. 11A wherein the positions of thedispensing mechanism, motor and cam are at a rest position. Theassemblies 102 and dosage form stack 48 rest upon the slider 124 whichis perpendicularly movable to the axis of the dosage form stack 48. Theslider 124 is a thin blade, with a thickness equal to or less than thatof a single dosage form, on axis with the dosage form stack. The slider124 slides between the end of the dosage form cartridge 102 and a solidface such that the spring 120 pushes the stack so as to place the firstdosage 48 against the solid face on the other side of the slider 124.The slider 124 includes a receiving portion 128 sized to accept thefirst dosage 48 opposite the cam. Exemplary cartridge dispensingmechanisms include column type, ribbon/tape type, disc type, helicaltype, barrel type, index/spring-load type, hopper type, conveyor type,continuous tablets type, shrink wrap type, snap-out type, track type,barrel lock type, adhesive tape, pocket tape type, a single doseapplicator, and foil on stack type.

A dispensing device of the present invention may dispense a dosage formby manual actuation of a button, lever, slider, wheel, or other actuatoror by a mechanism selected from the group consisting of mechanicalactuation, electro-mechanical actuation, spring loaded actuation,pneumatic actuation, hydraulic actuation, magnetic actuation,gravitational force activation, thermal actuation, combustive actuation,phase change expansion or contraction actuation, sonic actuation, andabsorbent actuation. The device may dispense a dosage form by means of amicroprocessor controlled actuator.

The dispensing mechanism for dispensing a drug dosage form may comprisea mechanical or electromechanical means for dispensing the drug dosageform.

FIGS. 11C and 11D are a schematic depiction of the dispensing device 100with the dispensing mechanism at a retrieval position. In the retrievalposition, the motor 106 turns the cam 108, retracting the slider 124,and allowing placement of the first dosage 48 in the receiving portion128. FIG. 11C shows the slider 124 retracted by means of a rotation ofthe cam 108, and displacement by the spring 118. In this position adosage form 48 is pushed by the spring 120 into the receiving cup 126portion of the slider 124.

FIGS. 11E and 11F are a schematic depiction of the dispensing device 100with the dispensing mechanism at a dispensing position for deliveringdrug dosage forms. In the dispensing position, the motor 106 turns thecam 108, extending the slider 124 with the first dosage form 48, andallowing dispensing of the first dosage 48. FIG. 11E shows the cam 108rotated so as to drive the slider 124 forward and dispense a dosage form48 past the sensor 114 and through the seal 112. The slider 124continues to move until such a point as the dosage form that has beenremoved from the stack is free to fall from the cup 126 or is forciblypushed from the cup 126 by the spring clip 116 and dispensed.

FIGS. 11G and 11H are depictions of the optical sensing mechanism fordetecting delivery of drug dosage forms of the dispensing device 100,wherein the position of a slider 124 and a drug dosage form 48 areillustrated. In this embodiment, the slider 124 includes a slot 130 forthe delivery sensors 114, so that the delivery sensors 114 will detectthe passing and delivery of drug dosage forms 48. When the slider 124pushes a dosage form 48 past the optical sensors 114, the opticalsensors 114 record an interrupted signal, indicating that a dosage formis present in the cup of the slider 124. If a dosage form 48 were notpresent in the cup of the slider 124 then the optical sensors 114 wouldnot record an interrupted signal, indicating that a dosage form 48 wasnot present.

FIGS. 12B-E provide a schematic depiction of push rod embodiments foruse in a dispensing device of the invention. The pushrod 3051 can beoperable to dispense a dosage form 3067. The push rod 3051 may betransparent 3107 (FIG. 12B); the push rod may have a opaque portion 3109with or without a window 3105 and with or without a reflector 3106 (FIG.12C); the push rod may have a transparent 3107 tip and an opaque pushrod portion 3109 (FIG. 12D); or have a transparent push rod portion 3107and an opaque tip portion 3109 (FIG. 12E). These approaches provide forvarious schemes for optical tablet and push rod position detection.

In yet another embodiment of the invention, a long tape or array ofdosage forms sealed between a flexible blister layer and a foil orotherwise breakable layer is provided. A pusher is positioned above adosage form, and upon actuation pushes against the blister, forcing thedosage form through the foil or breakable layer, dispensing the dosageform.

FIGS. 13A, 13B and 13C depict an additional embodiment of the dispensingdevices of the invention, wherein a ribbon type dispensing mechanism 134is illustrated. FIG. 13A depicts the dispensing mechanism at the restposition, FIG. 13B depicts the dispensing mechanism at retrievalposition, and 9C depicts the dispensing mechanism at dispensingposition. The mechanism includes a long tape or array of dosage formsadhered to one face with an adhesive. To dispense a dosage form 48, thetape 136 is rolled rollers 140 such that the surface with the dosageforms 48 adhered to it forms a convex shape, causing the dosage forms 48to peel off of the adhesive. In the embodiment shown, a peeler blade 142may be incorporated to assist in removing the dosage form 48 from theadhesive.

FIG. 14 depicts an additional embodiment of the dispensing mechanism134, wherein a different shape of a peeler blade 150 is shown. Inanother embodiment, gas pressure may be used to assist in removing thedosage form 48 or force a single dosage form 48 from the dispensingmechanism 134. To dispense a dosage form 48 the tape 136 is rolled on aroller 140 such that the surface with the dosage forms adhered to itforms a convex shape, causing the dosage forms 48 to peel off of theadhesive. A peeler blade may be incorporated to assist in removing thedosage form from the adhesive tape 136. A peeler blade 150 may beincorporated to assist in removing the dosage form 48 from the adhesive

FIGS. 15A and 15B depict yet another embodiment of the dispensingdevices of the invention, wherein a disc type dispensing mechanism 152utilizing a disk cartridge 146 is shown at a rest position (FIG. 15A)and at a dispensing position (FIG. 15B). The dispensing mechanism 152includes a lever handle 150 with teeth that engage a gear 151, arack/pusher 153, and a channel 154 in a housing, and a spring 156. Thechannel 154 provides space for the rack/pusher 153 to freely move withinthe channel 154. In FIG. 15A, the rack/pusher 153 is ready to push adosage form 48. As the lever handle 150 is pushed, the spring 156 iscompressed and the gear 151 rotates and the rack/pusher 153 engages thedrug dosage form 48. The drug dosage form 48 is pushed within thechannel 154. FIG. 15B shows the dosage form 48 being dispensed from theend of the channel 154 and into a subject, such as human. Then the stepsare repeated for successive dispensing of the dosage form 48.

The dispensing mechanism 152 consists of the following: a dispensingtrigger 150, a return spring 156, a gearing reduction 151, a pusher 153,a disk cartridge 146, a circular cam/ratchet 145, a dosage form 48, ahousing 144, and a seal 143. When the trigger 150 is depressed, drivingthe gearing reduction 151, the pusher 153 is driven through a diskcartridge 146 in such a manner that the pusher 153 drives a singledosage 48 from the disk cartridge 146. The disk cartridge 146 isfabricated with individual dosage compartments arrayed around theperimeter of the disk, and sealed with foil on both faces so as toindividually seal and package the dosage forms 48. As the pusher 153 isdriven through the disk cartridge 146, it breaks the foil seals on eachface, pushing the dosage form 48 out of the disk cartridge 146, througha seal 143, and delivering it from the dispenser housing 144.

FIG. 15B depicts an additional means of dispensing drug dosage forms,wherein a disc type dispensing mechanism in a dispensing position 154 isillustrated. This figure depicts the pusher 153 in a dispense positionafter it has pushed a dosage form 48 out of the disk cartridge 146 andthrough the seal 143. After the dosage form is delivered from thehousing 144, the return spring 156 returns the mechanism and a circularcam/ratchet 145 indexes the disk cartridge 146 by rotating it so thatthe next dosage form 48 is in position for the next delivery.

A disk delivery and indexing mechanism may be employed to deliver a drugdosage form from a dispenser of the invention. A disk delivery mechanismmay be manually or electro-mechanically actuated, and my use leadscrews, gears, mechanisms, linkages, rotary drives or any other means ofadvancing that enables the delivery mechanism to deliver a dosage form.The indexing ratchet may be achieved by means of a circular cam, anescapement, a lead screw, a gear train, a linkage, a stepper motor orother motor drive or any other means of indexing a disk.

A dispensing device may be pre-filled with a number of drug dosage formsin such a manner that the device is purchased and stored with thedosages in the device, or it may be filled on site at a pharmacy, or itmay be filled on the hospital floor by a nurse or other healthcareprofessional. The dosage forms may be packaged as a group of tablets ina bottle, vial, or other container, or they may be packaged in acontrolled orientation in a drug cartridge. The drug cartridge maycontain the doses in any configuration, including a stack, a row, acircular disk, a circular-arc disk, a strip, ribbon, tape, helix, or anarray or combination of any of the above, for example a multitude ofstacks of doses arranged in a geometric array. The invention furtherprovides additional methods of dispensing drug dosage forms which mayinclude combinations of these or other mechanisms. For example, a systemmay contain a shuttle to remove a dosage form from a stack, and a pusherto forcibly push the dosage form out of the system.

FIGS. 16A-16C depict an exemplary pushrod 158 designed for dispensing adrug dosage form 48. The pushrod may be made from any suitable material,for example, stainless steel.

FIGS. 17 and 18 depict other exemplary dispensing mechanisms withpushrods for dispensing drug dosage forms, wherein the pushrods aredesigned to be flexible. FIG. 17 shows dispensing mechanism 174 forsingulating and advancing a drug dosage form 48 through a nonlinear orlinear pathway by means of a flexible shaft 176 attached to an advancingmechanism, such as a rotation hub, such that advancing or retracting theflexible shaft within the nonlinear or linear pathway allows for thedispensing of a tablet or other dosage form 48 through the nonlinearpathway. FIG. 18 shows dispensing mechanism 180 for singulating andadvancing a drug dosage form 48 through a nonlinear or linear pathway bymeans of a flexible shaft 182 attached to an advancing mechanism, suchas a rotation hub, such that advancing or retracting the flexible shaftwithin the nonlinear or linear pathway allows for the dispensing of atablet or other dosage form 48 through the nonlinear pathway.

In a related approach, the drug delivery device of the inventioncomprises a tubular cartridge containing the stack, a spring pushing thestack, a solid face, and a slider or pusher, similar to the embodimentdescribed above. In this embodiment, the slider or pusher lacks a hole,but rather retracts from beneath the dosage form stack such that thespring can push the dosage forms up against the solid face. Duringactuation the pusher, which has a thickness equal to, larger than, orless than that of a single dosage form, pushes the first dosage form inthe stack perpendicular to the cartridge and dispenses it out of theside slot.

In another embodiment of the invention, dosage forms are dispensed bymoving a dosage form stack which is mounted with a pusher at one end andan elastomeric diaphragm retaining the opposite end of the dosage formstack. The diaphragm contains an orifice or hole or slot at the locationof the first dosage form. Upon actuation, the pusher pushes the stackand a single dosage form emerges from the diaphragm hole, at which pointthe pusher retracts slightly to allow the elastomeric diaphragm tore-seal and close again. The elastomeric diaphragm may be a seal orwiper type seal.

FIGS. 19A-19D provide schematic depictions of exemplary drug cartridgesincluding barrel type cartridge 224, index/springload type cartridge230, snap-out type cartridge 244, and track type cartridge 250. FIG. 19Adepicts a barrel type cartridge 224 which dispenses drug dosage forms 48stacked in each barrel 228 and rotates upon each actuation. FIG. 19Bdepicts an index/springload type cartridge 230. When a pusher 234 ispressed upon a rack 232, a spring 240 is used to minimize compressionexerted on the drug dosage forms 48 stacked in the cartridge 242 and apushrod 238 pushes the dosage forms 48 to dispense. FIG. 19C depicts asnap-out type cartridge 244. In the cartridge 244, a stick holding drugdosage forms 48 is moved toward a pushrod 248 and the pushrod 248 pushesthe drug dosage form 48 and snaps on the stick when dispensing iscompleted. FIG. 19D depicts a track type cartridge 250. Drug dosageforms 48 stacked in the track are dispensed.

Calibration

The dispensing device may be capable of self-calibration of the dispensemechanism, or the device may be calibrated manually. This process mayemploy a shipping tablet with a feature or features that physicallydifferentiate it from a drug dosage form or the push rod. These featuresmay be designed so that device calibration precision is higher that thatattainable using a dosage form or push rod. The differentiating featuremay be physical, optical, radio frequency (RF), electronic or magnetic.

FIG. 20 is a schematic depiction of an exemplary dispensing deviceshowing the stages of push rod/dosage form interaction during deviceuse. In FIG. 20, the push rod 5051, dosage forms 5067, shipping tablet5069, spring 5073 and position sensor 5071 are shown. During use, thepush rod 5051 moves between positions 5057, 5059, 5061, 5063 and 5065,also shown in FIG. 20 and further detailed in FIGS. 21A-D.

FIGS. 21A-D provide a series of flow diagrams for use of an exemplarydevice of the invention showing pusher logic, wherein FIG. 21A shows theLOAD feature; FIG. 21B shows the device calibration logic flow.Referring to FIG. 20, the pushrod 5051 is advanced from position 5065,picks up the shipping tablet 5069 at position 63, and is furtheradvanced to position 5061. At position 5061, the device senses thepresence of the shipping tablet 5069 and/or push rod 5051. In doing so,the device is calibrated and knows the location of the shipping tablet5069 and/or end of the push rod 51 regardless of assembly tolerances,variations in push rod length and push rod end conditions. Followingthis calibration, the push rod 5051 advances the shipping tablet 5069from position 5061 to position 5057 where the shipping tablet 5069 isdispensed from the device. During this operation, the device is able todistinguish between a shipping tablet 5069, a push rod 5051, and a drugtablet 5067. This differentiation enables the device to confirm that acartridge is unused because a shipping tablets is the first thingdispensed from a new cartridge during device setup. The feature thatprovides the means for differentiating between the shipping tablet, pushrod, and tablet 5067 may be optical, physical, RF, electronic(resistive, capacitive, or other) or magnetic. In addition, this featuremay be designed to provide a means for greater device calibrationprecision than that attainable using a tablet or push rod. The push rod5051 advance from position 5065 and position 5057 described above, couldbe continuous or intermittent and a physical stop at position 5061 isnot required. The push rod 5051 then retracts from position 5057 toposition 5059, placing the device 11 in the ready position with the pushrod 5051 under the remaining dosage forms 5067. In this position, thepush rod 5051 keeps dosage forms 5067 from inadvertently falling out ofthe device.

FIG. 21C shows the device dispense logic flow. Referencing FIG. 20,following a dose command, the push rod 5051 retracts from position 5059to position 65, allowing the dosage forms 5067 to advance into the pushrod track. The push rod 5051 then advances from position 65, picks up adosage form at position 5063, and then dispenses the dosage forms 5067from the device at position 5057. Between positions 5063 and 5057, thepresence of a dosage form 5067 is sensed/confirmed at position 5061 bythe position sensor. The push rod then retracts from position 5057 toposition 5059, placing it in the ready position with the push rod 5051is under the remaining dosage forms 5067. In this position, the push rod5051 is allowed to dry before the next dosage form 5067 dispense, aswell as keeps dosage forms 5067 from inadvertently falling out of thedevice.

FIG. 21D shows the device disassemble logic flow. Following a“disassemble” command, the push rod 5051 is moved to position 5065. Thisallows for the removal of any remaining dosage forms 5067 without pushrod interference.

Dosage Forms Delivered with the Dispensing Device of the Invention

Oral transmucosal drug delivery is effective, easy to deliver,non-invasive, and can be administered by the caregiver or the patientwith minimal discomfort. Generally, oral transmucosal delivery ofpharmaceuticals is achieved using solid dosage forms such as lozenges ordosage forms, however, liquids, sprays, gels, powders, gums, foams,patches, and films may also be used. A drug dispensing device of thepresent invention provides a means to deliver a small-volume drug dosageform that is adapted for delivery of the drug via the oral mucosa.

In one embodiment, a drug dispensing device of the invention provides ameans to deliver dosage forms for oral transmucosal delivery ofpharmaceutically active substances. The dosage forms may be solid ornon-solid and may serve as a delivery vehicle for any medication, e.g.,a pain-relieving drug such as an opioid or an opioid agonists, or drugsfor treating angina, anxiety, insomnia, ADHD, addiction, nausea, and soon. Solid dosage forms, such as sublingual dosage forms, troches,lozenges, powders, and films that can be used to deliver drugs via theoral mucosal tissue are considered to be within the scope of theinvention.

The invention also encompasses drug dispensing devices for delivery ofother non-solid dosage forms such as gels, salves, pastes, mists,liquids, aerosols, gases, vapors, foams, emulsions, sprays, suspensionsand the like.

In one embodiment, a drug dispensing device of the invention provides ameans to deliver small-volume drug delivery dosage forms, exemplifiedherein for the treatment of pain. In this embodiment, the dosage form isdesigned to remain in the sublingual area, adhering to the oral mucosa,and is small enough to elicit little or no saliva response from thepatient. Although the dosage form is intended to remain in thesublingual space, it will be effective when absorbed through any oraltransmucosal route.

In one embodiment, a drug dispensing device of the invention is used foradministration of a small-volume drug delivery dosage form for oraltransmucosal delivery of drugs, wherein the dosage form is prepackagedand is self-administered. The invention also encompasses use of thedevice to deliver a small-volume drug delivery dosage form for oraltransmucosal delivery of drugs that are not prepackaged.

A means for minimizing saliva influx into a dispensing device for oraltransmucosal administration of a drug dosage form comprises seals,wipers, absorbants, air gaps, desiccants, and multiple stage deliverysystems. The dispensing device dispenses the drug dosage form one at atime without adversely affecting other drug dosage forms contained in acartridge filled with the drug dosage form.

In one preferred embodiment, a drug dispensing device of the inventionprovides a means to deliver a drug dosage form that is generally verysmall, e.g., a NanoTab®. The NanoTabs® may be used to deliver any drugthat may be administered by the oral transmucosal route in an amountamenable to administration via the small size of the NanoTabs®, i.e.about 0.1 mg to about 99.9 mg. In one preferred embodiment, the NanoTab®is adhered sublingually.

The dosage form will typically comprise 0.01%-99% w/w of the activeingredient(s) percent by weight of the active ingredient or “drug”. Theterm “drug” as used herein means any “drug”, “active agent”, “active”,“medication” or “therapeutically active agent”. In some embodiments, thedosage form is a NanoTab®, which may be used to deliver any drug thatmay be administered by the oral transmucosal route in an amount amenableto administration via the small size of the dosage form, e.g., up to99.9 mg of drug, for example, 0.25 μg to 99.9 mg, 1 μg to 50 mg or 1 μgto 10 mg of drug.

The shape of a drug dosage form for use in practicing the invention ispreferably approximately disc-shaped, but may be rectangular, square,polygonal, oval or spherical, any combination of these, or may benon-symmetric. When disc-shaped, the flattened surface provides anincreased surface area for adhesion and drug elution. The drug dosageform may be formed in any geometry that may be delivered using a drugdispensing device of the invention. Optimally the drug dosage forms areformed as round discs with flat, concave, or convex faces. Alternately,they may be ellipsoids with flat, concave, or convex faces, or polygonswith 3 or more edges and flat, concave, or convex faces. The drug dosageforms may also be spherical, ellipsoidal, or have the shape of any othercurved solid body. The drug dosage forms may also be any non-symmetricalshape and may enable specific handling and orientation in the dispenserdevice and during placement.

FIGS. 22A and 22B provide depictions of exemplary drug shapes. FIG. 22Ais a schematic depiction of symmetric drug dosage forms 368 includinground discs with flat, concave, or convex faces, ellipsoids with flat,concave, or convex faces, spherical, polygons with 3 or more edges andflat, concave, or convex faces, or any other curved solid body. FIG. 22Bis a schematic depiction of other drug shapes 370 in asymmetric dosageforms.

In one exemplary formulation, the dosage form is approximatelydisc-shaped, the volume of the drug dosage form is about 5 microliters,and the dimensions of the drug dosage form are approximately 0.85 mm inthickness, and 3.0 mm in diameter.

A drug dispensing device of the invention will provide a number ofdosage forms that will vary according the nature and amount of activeingredients while maintaining the size and features appropriate forefficacious delivery.

A device of the invention can be loaded with many days worth ofmedication (e.g., 30 days or more) at one time, and may require nospecial packaging for the medication. Alternatively, the medication maybe provided in the form of a pre-filled cartridge.

The present invention provides the advantage that the drug is deliveredvia a dispensing device which provides for the dispensing of multipledosages of a small-volume oral transmucosal drug delivery dosage formsuch that the appropriate dose and frequency for therapeutic efficacymay be obtained, while simultaneously providing a timed lock-out featureto prevent accidental overdosing. The dose and corresponding lock-outtime may be adjusted dependent upon the size of the subject and theintended therapeutic goal.

As set forth above, a drug dispensing device of the invention comprisesa means for minimizing saliva influx into the device when used for oraladministration. In this embodiment, he dispensing device dispenses thedrug dosage form one at a time without adversely affecting other drugdosage forms contained in a cartridge filled with additional drug dosageforms. A means for trapping or otherwise isolating saliva or moistureonce it has entered the device may include but is not limited to ahydrophilic wicking material or component, an absorbent or adsorbentmaterial or component, or a desiccant material or component, or anycombination of these materials or components.

The drug dosage form dispenser of the invention may dispense drug dosageforms or it may dispense drug dosage forms attached to or containedwithin a disposable applicator with means of allowing manual applicationof said dosage form to a pre-determined location for drug delivery (e.g.the mouth, sublingual space, the eye, etc.). In one embodiment, a singledose applicator may be used for a variety of drug dosage forms,including a solid tablet, a liquid capsule, a gel capsule, a liquid, agel, a powder, a film, a strip, a ribbon, a spray, a mist, a patch, orany other suitable drug dosage form. The single dose applicator (SDA)may contain the dosage form within, may have the drug dosage formattached or affixed to it, may afford a seal against moisture, humidity,and light, and may be manually manipulated by a patient, healthcareprovider, or other user to place said dosage form in the proper locationfor drug delivery. The SDA may be of the form of a pair of forceps, asyringe, a stick or rod, a straw, a dropper, a sprayer or atomizer, orany other form suitable for the application of a single drug dosageform. After use, said SDA may be disposed of, so as to eliminate therisk of contaminating the dispenser with saliva, or other contaminants.

The present invention provides disposable single dose applicatorscomprising a blister pack 3151, which contains drug dosage forms 3067inside a housing and a handle 3131, wherein a backing, such as a foilseal 3135 covers the dosage form 3067 and the handle 3131, as shown forexample in FIGS. 23B and 23D.

FIG. 23A shows an embodiment of a single dose applicator 3123 that iscomprised of a applicator shaped as a tube 3129, a stopper seal 3127, ahandle 3131 (e.g., an ergonomic handle), and a single dosage form 3067.The tube 3129 defines an opening 3133; the stopper seal 3127 can beremoveably coupled to the tube 3129 obstructing the opening 3133.

In one embodiment, the disposable single dose applicator, thecombination of housing or tube 3129 and handle 3131 has the shape of aspoon.

The housing or tube 3129 for the dosage form 3067 is a blister pack 3151that accommodates a unit dose of a dosage form 3067 for administrationto a subject. The dosage form 3067 is sealed in the blister pack 3151 bya foil or other type of seal 3135 backing.

In some embodiments, the foil or other type of seal 3135 is removedprior to administration of the dosage form 3067 and the handle 3131 isused to place the dosage form 3067 in the appropriate location againstthe oral mucosa of the subject such that the dosage form 3067 adheres tothe oral mucosa. See, e.g., FIGS. 23B, 23D, 23E and 23F. In otherembodiments, the foil or other type of seal 3135 is perforated andremoved prior to administration of the dosage form 3067 by folding theapplicator 3123 at the perforation 3149 prior to administration wherethe handle 3131 is used to place the dosage form 3067 in the appropriatelocation against the oral mucosa of a subject. See, e.g., FIGS. 26A andB. This permits the handling of only a single drug dosage form 3067 at atime and prevents the other individually sealed drug dosage forms 3067from becoming exposed to saliva, humidity and the like.

The foil or other type of seal 3135 of a disposable applicator 3123including handle 3131 is typically made of a single piece of foillaminate, paper, plastic or other covering, i.e. an applicator tab 3147that spans the back of the housing or tube 3129 alone or both thehousing or tube 3129 and the handle 3131, effectively seals the dosageform 3067 in a blister pack 3151 or other container.

The handle 3131 enables proper placement of the dosage form 3067 withouttouching the dosage form 3067.

A plurality of single dose applicators may be provided as a series ofindividual single dose applicators attached by the backing or housed inmultiple dose dispenser 3137.

In another embodiment, a dispensing device 3011 comprises a package 3141that holds a single or multiple drug dosage forms, a distal orifice fordelivery of the drug dosage form, and an internal mechanism thatsegregates and releases the dosage forms. See, e.g., FIG. 24. Thedispensing device is typically handheld and may comprise some or all ofthe features set forth above for a device used to dispense non-packageddosage forms.

FIGS. 27A-B are schematic depictions of exemplary single doseapplicators 3123 for delivering dispensing drug dosage forms 3067,wherein exemplary single dose applicators are shown. When the applicator3123 is positioned for delivery and is squeezed 3125, as shown in FIG.27B, a flexible hinged section deforms, allowing the dosage from 3067 tobe released on an oral mucosal membrane, e.g., into the sublingualspace. After applying the dosage form 3067, the drug dispensing devicemay be disposed.

FIGS. 27A and 27B show one embodiment of a single dose applicator 3123 adispensing device for delivering drug dosage forms. The dispensingdevice shown in FIG. 27A depicts the single dose applicator 3123 that isready to dispense a drug dosage form 3067. In one aspect of thisembodiment, a user pinches the single dose applicator 3125 which opensthe applicator and a drug dosage form 3067 is dispensed as shown in FIG.27B.

FIGS. 23A-F, FIGS. 25A-C, FIGS. 26A, and B FIGS. 28A-C are schematicdepictions of exemplary embodiments of a SDA of the invention.

FIGS. 23A-F show several alternate embodiments of the single doseapplicator 3123. In all of these figures the applicator seal 3127 isbroken and the applicator is tilted so as to drop the drug dosage form3067 on an oral mucosal membrane in the mouth of a subject, e.g., underthe tongue for sublingual dosage form placement. FIG. 23A shows a tubelike applicator 3129 with a handle 3131 located axially under the tube3129. FIG. 23B shows an applicator formed as a thermoform or blisterpackage 3151 with a foil seal 3135 that is peeled so as to open theapplicator package 3141 prior to placing the dosage form 3067. FIG. 23Cshows an applicator that is a tube 3129 which is broken to break theseal prior to dosage form 3067 placement. FIG. 26D shows a blister packtube 3151 type dosage form package 3141 with a handle 3131 such thatafter the seal 3135 is peeled back the blister pack 3151 can be held andtilted to place the drug dosage form 3067, on an oral mucosal membrane.FIGS. 23E and 23F show blister pack 3151 type packaging with a handle3131 shaped like a flower or an animal, respectively, to be used forsingle dose applicator 3123 designed for pediatric use. Other singledose applicator shapes could include cartoon characters, animals,super-heroes or other appropriate shapes for pediatric applications.

FIG. 25A shows a flat rigid applicator 3123 with a dosage form 3067adhered to one end, for example, by means of a rapidly dissolvingingestible adhesive material 3139 such that when the applicator end withthe dosage form is placed under the tongue, the adhesive dissolves, thedosage form 3067 is placed on an oral mucosal membrane, such as in thesublingual space, and the applicator can be removed. FIG. 25B shows anapplicator 3123 made from a water permeable material, impregnated withdrug, forming a material and dosage form matrix. When the impregnatedend of this applicator is placed under in the mouth on the oral mucosa,the moisture in the saliva dissolves the drug and delivers ittransmucosally. FIG. 25C shows a dissolving film dosage form 3145 and adosage form package with a plurality of dissolving film dosage forms3143 within it. The dissolving film dosage form 3143 is removed from thepackage 3141 and placed on an oral mucosal membrane, e.g., in thesublingual space where it dissolves and delivers the drugtransmucosally.

FIGS. 26A-B provide illustrations of two stages of use of one embodimentof a single dose applicator 3123. FIG. 26A shows the applicator 3123 inits configuration prior to use, with the following features: applicatortab 3147, perforation 3149, and blister pack 3151 containing a dosageform 3067. In order to administer the dosage form 3067, the applicatortabs 3147 are bent downward at the perforations 3149, and the seal 3135is peeled back to reveal the blister pack 3151 and allow the dosage form3067 to be dropped on an oral mucosal membrane, e.g., in the sublingualspace.

FIGS. 28A-C show an embodiment of a single dose applicator 3123 that iscomprised of a applicator shaped as a tube 3129, a stopper seal 3127, ahandle 3131 (e.g., an ergonomic handle), and a single dosage form 3067.FIG. 28A shows the single dose applicator 3123 in its sealedconfiguration, prior to use. FIG. 28B shows the single dose applicator3123 with its stopper seal 3127 removed, forming an opening 3133, andready for use. FIG. 28C shows the single dose applicator 3123 tilted soas to dispense the dosage form 3067 on the oral mucosa, e.g., in thesublingual space.

The invention provides exemplary dispensing devices with a singulatordispensing mechanism including a reusable single dose applicator. Thesingulator dispensing mechanisms may include the following; a reusablesingle dose applicator; a foil blister; rotating stations; a disk withejectors; a ribbon peeler; a ribbon picker; disk singulators; a flexibledisk; an arc or helical type single dose applicator; a pushrod stackejector; and a rotating stack ejector.

In another embodiment, a drug dispensing device of the invention maycontain a plurality of SDA's, in a cartridge or individually packaged,and may dispense a single SDA containing a single drug dosage form foruse by the patient, healthcare provider, or user. The drug dispensingdevice may dispense single SDA's in the same way and with the samefeatures as would be advantageous for the dispensing of single drugdosage forms described in the invention.

In yet another embodiment the multiple dose applicator 137 comprises oneor more drug dosage forms 67 or single dose applicators 123, a portablepower means, like a battery, a printed circuit board, a dataconnectivity means, and a user interface. In this embodiment the drugdispensing device may include the ability to perform one or more of thefollowing functions: record drug dosage dispensing history, check useridentification by means of fingerprint identification, RFID, voicerecognition, etc., allow the dosage history to be transferred to anotherdevice, computer or network, and/or provide a lockout period betweendose dispenses.

FIG. 24 is a schematic depiction of an exemplary multiple doseapplicator 3137 for delivering dispensing drug dosage forms 67, eachindividually packaged in a single dose applicator 3123.

Dosing History/Feedback

Further embodiments of the device include the ability to storehistorical use information and the ability to transmit such information.The device may be capable of unidirectional (downloading) orbidirectional information transfer. For example, an exchange ofinformation may be accomplished by downloading stored information to acomputer through a physically wired interface, such as a USB or anyother communication connection. Alternatively, information may becommunicated via a wireless system.

In another embodiment, the dispensing device has a dose counting featurethat monitors and stores the history of drug usage. Such information mayinclude historical use information, for example the number of dosagesstored and dispensed, and the times of dispensing.

Lock Out

The dispensing device provides for lock out, requiring the patient tocommunicate with the physician or other authorized care giver to unlockthe device for the next fixed period. In this way the device and dockprovide for safe drug administration due to greater physician oversightand care management.

The dispensing device provides a means for adjusting both the initialdose and subsequent doses, as well as the lock-out time. The initialdose and lock out time may subsequently be adjusted dependent uponpatient response, duration of treatment and the like.

The initial timed lock-out period for a claimed dispensing device istypically from about 1 minute to about 60 minutes, from 3 minutes to 40minutes or from 5 minutes to 30 minutes, and in particular cases is setat any one minute interval from 1 to 60 minutes, e.g., 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes.

In some cases, a dispensing device has a fixed lockout between doses andmay exhibit a shutdown after a fixed period of time. In other cases, thelock-out time is a programmable lock-out time. The lock-out time mayalso be a fixed time lock-out interval, a predetermined lock-outinterval, a predetermined variable lock-out interval, a lock-outinterval determined by an algorithm or a variable lock-out intervalcommunicated to the device from a remote computer or docking station.

The dispensing device may include a lockout feature that prevents dosingthe drug in an unsafe or non-prescribed manner. This lockout feature maymechanically prevent the device from dispensing a dose by either lockingthe mechanism, disengaging a component of the mechanism, or bycontrolling the dispensing mechanism by means of a microprocessor and analgorithm during the lockout period. The lockout may be of a fixedperiod (10 minutes, for example), of a predetermined variable period, a“smart” variable period, or a “triggered” lockout based on an internalor external event or state. The fixed lockout would afford a fixedlockout period after each dose, wherein the device will not allow asubsequent dose to be delivered. The pre-determined variable lockoutwould afford a variable lockout period after dosing, following apre-determined lockout schedule (for example, the lockout period mayincrease by one minute following each subsequent dose). The “smart”lockout would afford a variable lockout period based on an internalalgorithm taking into account the dosing history, dosing requests, orany other data or inputs that the algorithm may use for determination.For example, the smart lockout may base the lockout period on the dosinghistory, taking into account the pharmacokinetics of the specific drugmolecule, and how the body naturally clears or metabolizes the drug overtime. The triggered lockout would respond to internal or externaltriggers, such as data from sensors (e.g. temperature, humidity, heartrate, respiratory rate, blood pressure), internal signals (date, time,or location from GPS), signals from external computers, networks, orother electronic devices, the presence of a physical, magnetic orelectronic key, the receipt of a mechanical or electronic access signalsuch as a password, code, RFID signal, or any other wired or wirelesssignal. The dispensing device of the invention may employ one or more ofthe lockout described herein.

In one exemplary embodiment, the dispensing device has a smart lockoutpreventing dosing of a tablet for a period of time following an initialdose, based on the dosing history and an internal algorithm. In thisembodiment the lockout time is calculated to predict the safe dosinginterval knowing the history of drug doses the patient has already takenand the pharmacokinetics of the drug.

In another exemplary embodiment, the dispensing device is programmed toallow dosing for the 72 hour recovery period following a minoroutpatient orthopedic surgery procedure. When the device is firstprescribed to the patient, the internal clock in the device begins totrack the elapsed time. When the elapsed time reaches 72 hours thedevice locks down, notifying the patient that the dispensing device hasexpired and will no longer allow dosed to be delivered.

In another exemplary embodiment, the dispensing device is programmed toallow dosing for the 72 hour recovery period following a minoroutpatient orthopedic surgery procedure. When the device is firstprescribed to the patient, the internal clock in the device begins totrack the elapsed time. When the elapsed time reaches 72 hours thedevice locks down, notifying the patient that the dispensing device hasexpired and will no longer allow dosed to be delivered.

The present invention may also provide a means for adjusting both theinitial dose and subsequent doses, as well as the lock-out time.Patients can be evaluated to determine the appropriate dosing scheduleand lock-out time following an evaluation of drug plasma concentration.

The dispensing device allows for a variable, pre-determined lockoutschedule that may vary with length of the prescription, time of day,progression of ailment or symptoms, etc. and may utilize an algorithm todetermine the lockout schedule and duration, based on prescription,medication, dosing history, and other patient specific information suchas vital signs (e.g., respiratory rate or blood pressure determined by anon-invasive means), taken together with pharmacokinetics of the activedrug agent.

If the patient does not achieve sufficient therapeutic benefit from asingle administration, the advantage of the repetitive dosing featurewith lock-out is that the patient can re-dose, thereby titrating theirplasma levels of drug in a safe manner. This can be repeated until atherapeutic plasma level is achieved.

An initial dose and lock out time for a dispensing device of theinvention is set upon initiation of treatment depending upon the age andweight of the patient and medical history. However, the initial dose andlock out time may subsequently be adjusted dependent upon patientresponse, duration of treatment and the like.

The present invention provides a dispensing device with a programmablelock-out feature for locking the dispensing device when the device islocked. This prevents or deters abuse or accidental or inadvertentmisuse. The lock-out feature operates by a means selected from the groupconsisting of a movable pushrod, a non-returning pushrod, anelectromechanical regulator, an optical sensor pair, a magnetic clutch,a lockout on actuator, a rack and pinion, a safety button latch, asolenoid, a collect on shaft, a keyed hubs, lead screw, rotary actuatoror mechanism, a movable coupling, and cams.

The present invention provides a dispensing device with an accesscontrol means for controlling abuse or accidental or inadvertent misuseother than by a healthcare professional. The dispensing device will notfunction if the cartridge is not loaded, locked-in, and activated by thehealthcare professional.

The dispensing device of the invention may be used multiple times or bedisposable such that it is discarded when all of the medicationinitially loaded into the device has been dispensed.

FIGS. 29A-29D are schematic depictions of one embodiment of a drugdispensing mechanism 84 which includes a lockout feature. The drugdispensing mechanism 84 includes a pushrod 86, a lock 88, abutton/pusher 90, and a wedge 92. In use, the button/pusher 90 pushesthe lock 88 into the pushrod 86. When the lock 88 is raised, thebutton/pusher 90 is unable to push it and the mechanism is locked. FIGS.29A through 29D illustrate various stages of a lockout mechanism relatedto dispensing drug dosage forms. FIG. 29A depicts a situation where apredetermined lockout period has not passed and the dispensing mechanism84 is still in locked position, with the lock 88 raised. In FIG. 29B, apredetermined lockout period has passed and the lock 88 is in thelowered position and the lockout mechanism allows the dispensingmechanism in dispensing position. FIG. 29C depicts a further step wherethe dispensing mechanism 84 operates with the button/pusher 90 pushingthe lock 88 into the pushrod 86 to dispense drug dosage forms (notshown). FIG. 29D depicts a locked position for a predetermined lookoutperiod for a next dispensing. The locking device may be attached to thedrug dispensing device to prevent unauthorized dispensing of themedication. Sensors may be located on the exit port to detect thesuccessful dispensing of a dosage form, which is recorded internally bythe dispensing device, or by a wired or wirelessly attached dock orcomputer. The types of the locking devices may include the following: amovable push rod; a non-returning push rod; an electromechanicalregulator; an optical sensor pair; a magnetic clutch; a lockout onactuator; a rack and pinion; a safety button latch; a solenoid; a colleton shaft; a keyed hub; a movable coupling; and a cam.

FIGS. 30A-30F are schematic depictions of exemplary lockout mechanisms.FIG. 30A depicts a pushrod type lockout mechanism 186. When a pushrod188 is pressed, a solenoid 190 reacts to a signal to move a return lock192 in a locking position, to prevent a dispensing device fromdispensing drug dosage forms 48 during a lockout period. FIG. 30Bdepicts an actuator type lockout mechanism 196. When a pushrod 200 ispressed in a lockout mechanism 196, a lock 198 moves in response to thepushrod's 200 movement with the help of solenoid 202 to lockout onactuator. FIGS. 30C and 30D depicts a safety button/latch type lockoutmechanisms 204 and 214, respectively. In the figures, a latch 206 locksa pushrod 210 in a locked position. A patient pushes the dispenser 212to reveal button 208 to unlock the latch 206. FIG. 30E depicts asolenoid type I lockout mechanism 216, wherein solenoid 217 moves tolock the device. Another solenoid type lockout mechanism 218 is shown inFIG. 30F. Solenoid 220 moves upon a button 222 being pressed and locksthe device.

Patient Identification Feature

In one aspect, the dispensing device comprises a detecting means forpatient identification such as a fingerprint reader, an optical retinalreader, a voice recognition system, a face recognition system, a dentalimprint recognition system, a visual recognition system, or a DNAreader. The dispensing device may employ one or more means to identifythe user, enabling the system to determine if a dispensing request isbeing made in an authorized or unauthorized manner. It is important foreffective delivery of many potential drugs and drug dosage forms toensure that the dispensing device is not accidentally or intentionallyused by an unauthorized individual to prevent accidental or intentionaldiversion of the drug. Such patient identification systems may recognizeone or more users, for example, in an inpatient hospital setting thedispensing device could be programmed to recognize the patient to whomit is prescribed, as well as authorized healthcare providers such asnurses and physicians. In an outpatient home setting, for example, thedispensing device may only respond to the patient to whom it isprescribed.

The dispensing device may employ any means of user identification,including fingerprint identification, RFID detection with the use of anactive or passive RFID tag on bracelet, necklace, clip, belt, strap,adhesive patch, implant, or means of locating and affixing a tag, retinaidentification, DNA identification, voice recognition, password or codeentry, physical key, electronic or magnetic key, personal area networkidentification using the human body or clothing as a data or signalconduit, optical scanner or face recognition, sonic, subsonic orultrasonic identification, or any other means of identifying anindividual and verifying their identity.

One method of patient identification is the use of a short distance(“near field”) passive RFID tag attached to a bracelet, necklace,adhesive patch, clothing tag, orally mounted device, like an orthodonticretainer, belt, strap, some combination of these, or another location.When an RFID tag is used in the “near field”, roughly defined as about16% of the wavelength of the received signal, the tag behaves in theinductive mode of operation, coupling between the reader and tag antennamagnetically. The near field is characterized by at least two features:first is a rapid decline in field strength with distance, and second isa strong directionality of the signal. In the near field, the signalstrength falls off very rapidly, with a signal strength loss ofapproximately 60 dB per decade in distance. For good inductive couplingbetween the transmitter antenna and the RFID tag antenna, the twoantennas are oriented in parallel planes with the axes through thecenter of each antenna in close proximity. Strong signal strength(robust patient identification) is provided when the device is veryclose to the RFID tag. At the same time, a very poor signal is providedwhen the device is further away from the tag, which helps preventunauthorized use by someone other than the patient who attempts to usethe device. It is preferable to operate in this near field region withgood antenna alignment. Furthermore, it is preferable to operate with avery short distance of adequate signal strength for a positiveidentification, so that it is very difficult to receive a signal if thedevice is not in the proper orientation and proximity to the RFID tag.To attain a short distance and a proper alignment between antennas, thedispensing device may be designed so as to properly locate the RFIDreader antenna, mounted in the dispensing device, adjacent to an RFIDtag antenna, mounted, for example, on a wrist band or bracelet, or aclothing tag on the collar, or an adhesive patch on the hand, arm,cheek, neck, or elsewhere. Furthermore, an RFID tag antenna on a wristband or bracelet may be held in proper alignment and location by meansof a small adhesive patch that prevents the bracelet from moving orrotation on the wrist.

In another embodiment, the dispensing device employs a high frequencyRFID reader for use in the inpatient (hospital, clinic, etc.) setting,operating on or near the 13.56 MHz frequency band, and the patient is befitted with a matching RFID tag and antenna on a disposable bracelet orwrist band, designed in such a way that if the bracelet or wrist band isremoved the RFID tag, the antenna, or another component of theassociated circuit will be damaged or destroyed, rendering the braceletor wrist band non-functional. In one example, the range of the RFIDcommunication is short, between 0 inches and 10 inches preferably, morepreferably between 0 and 5 inches, and most preferably between 0 and 3inches, and may additionally be directional, allowing proper use by theintended patient to be easy and reliable, while at the same time makingunauthorized use by another individual difficult, very difficult, orimpossible.

In another embodiment, a dispensing device of the invention for use inthe outpatient setting (e.g. home, office, etc.) includes an electronicfingerprint sensor system and would be trained to identify the patient'sfingerprint at the time of prescription or first use.

Additional Features

A dispensing device may provide the ability to recognize a specificcartridge by a mechanical, optical (e.g. bar code), electronic (e.g.microchip), magnetic, radio frequency, chemical, or other means ofdetecting and identifying the cartridge. In one exemplary embodiment,the drug-containing cartridge contains a physical keying detail on thecartridge that is physically detected by a sensor or switch or a seriesof sensors or switches in the dispensing device. Furthermore, thedispensing device may communicate uni-directionally or bi-directionallywith the cartridge to exchange information. Such information may includedrug name, dosage strength, usage information, lockout period,manufacturing lot number, indications for use, side effects, druginteractions, date of manufacture, date of expiration, serial number,number of doses in the cartridge, or any other relevant information. Thedispensing device may be able to write, in addition to read, informationto the cartridge, like date used, nurse or patient identification,number of doses used, etc.

The dispensing device may provide mechanical protection for the dosageforms contained therein, preventing breakage, chipping, hydration etc.,thereby allowing for dispensing of the undamaged dosage forms containedtherein. This is of particular importance for small fragile and friabledosage forms.

The drug dispensing device may be powered by a battery, capacitor, fuelcell, or other power supply source, or may require no electrical power,but be manually activated.

In one embodiment, the dispensing device of the invention includes ameans to produce an audible, visual, or tactile signal when the drug isadministered (such as a click, beep or visual indication such as alight) to provide feedback to the patient that a dosage has beendispensed. In the example of a small sized dosage from such as aNanoTab® dosed sublingually, the patient may not be aware of the drug intheir sublingual cavity, therefore another means of feedback may benecessary. The present invention provides a solution to meet this need.

A dispensing device of the invention may be manufactured in an array ofcolors that correlate to the array of unit doses to allow for easyidentification of drug dose. The device may have other visual, audible,or tactile identifiers to communicate the dosage contained therein.

The dispensing device of the invention finds utility in the dispensingof one or more medications, and in some embodiments provides a pluralityof dispensing devices which comprise more than one drug, drug dosage,drug form, etc. In a similar fashion the dispensing device may contain aplurality of dosage forms, in a plurality of cartridges, dispensed bymeans of multiple mechanisms and delivery channels, etc.

The dispensing device of the invention includes an architecture thatallows refilling of the drug dosage form by an approved or authorizeduser (such as a doctor, nurse, pharmacist or other medical personnel),while denying access to unapproved individuals.

In other embodiments, the dispensing device of the invention includes adisposable tip that contacts the patient's body or mouth, so that thedevice may be used with multiple patients without the risk of crosscontamination.

In some embodiments, the dispensing device is capable of issuing alarmsor other notifications when functional or safety issues arise. The alarmor other notification may trigger an alert on the dispensing device, ona dock or other peripheral device; on a computer or by means of a wiredor wireless network, or may alert other remote devices. The alarm ornotification may be audible, tactile, visual, or may employ other meansof notifying one or more individuals.

Docking Station

In certain embodiments, the device includes a portable or fixed dockingstation that may query the device, reset it between dosing, lock it whennot properly accessed, and control the dosing regimen. The drugdispensing device may communicate with a physician or care giver, viathe dock; or by a wired or wireless communication means.

In yet another embodiment, the dispensing device is adapted to have theability to track and communicate the total number of doses remaining inthe device to allow anticipation and scheduling of refilling. Thedispensing device also may include the ability to record and track drugusage and communicate this, optionally via wireless protocols or byelectronic docking, to a healthcare provider to monitor the patient'sdrug use.

In some embodiments, the dispensing device may be remotely programmed toallow physician oversight and care management. It may include a radiofrequency identification (RFID) system, WiFi communication, or otherremote operation system that provides a means of communication andcontrol of the device to allow remote monitoring of error codes, dosinghistories, patient use histories, remaining doses, battery levels, etc.Such a system may include a unique key for each device that must beproximal to the device for operation, so as to prevent accidental orintentional tampering, abuse, or access to the drug by an unauthorizedindividual. Such a remote operation system may also provide a unique keylocated at the patient's bedside, possibly in a stand or dock, orattached to the patient or his or her clothes, possibly on a bracelet,necklace, adhesive patch, or clip, to avoid accidental or intentionalswapping of devices between patients or other accidental or intentionaldiversion.

In embodiments where a dispensing device of the invention is used todispense a controlled substance such as an opioid, the dispensing devicemay be designed in such a way as to provide containment of an opioidantagonist in a configuration that prevents intentional diversion. Thedispensing device may be equipped with a small liquid opiate antagonistreservoir that is held at slight pressure, and biased to dump theantagonist into the dosage form cartridge. The powered up systemactively prevents the antagonist reservoir from flooding the cartridgeby means of a valve or other controllable conduit. In the event of apower failure, major physical damage, or malicious tampering, theantagonist reservoir will dispense the opiate antagonist into thecartridge, rendering the dosage forms unsuitable for use. In thisembodiment, the dispensing device provides, for example, in a liquidform, in a separate reservoir that will mix with the drug formulation inthe event of a power or system failure, device damage or tampering.

In some embodiments, a spoiling agent is used in place of theantagonist. If the dispensing device is forced open, the spoiling agentwill contact and contaminate the drug formulation, making it unsuitablefor any non-approved use.

To protect the drug dosage forms from exposure to moisture either fromhumidity, saliva ingress, or accidental exposure to other water basedliquids, the dispensing device and the container or cartridge whichhouses the dosage form within the device may contain a desiccant. Amechanism to prevent saliva ingress includes inclusion of a desiccant,seals, absorbents, adsorbents wipers, and sensors. A desiccant is asorbant, in the form of a solid, liquid, or gel that has an affinity forwater, and absorbs or adsorbs moisture from the surrounding, thuscontrolling the moisture in the immediate environment. Any commercialdesiccant which typically, take the form of pellets, canisters, packets,capsules, powders, solid materials, papers, boards, tablets, adhesivepatches, and films, and can be formed for specific applications,including injection moldable plastics find application in practicing thepresent invention. There are many types of solid desiccants, includingsilica gel (sodium silicate, which is a solid, not a gel),alumino-silicate, activated alumina, zeolite, molecular sieves,montmorillonite clay, calcium oxide and calcium sulfate, any of whichmay be used in practicing the present invention. Different desiccantswill have different affinities to moisture or other substances, as wellas different capacities, and rates of absorption or adsorption. Also,different types of desiccants will come to equilibrium at differentrelative humidities in their immediate surroundings. As a means forprotecting the dosage forms and the internal portions of a dispensingdevice of the invention from moisture, one or more desiccants may beemployed at the dispensing tip, in or adjacent to the dosage form, e.g.,tablet, delivery pathway, in or adjacent to the dosage form, tabletcontainer or cartridge, in or adjacent to other components of thedispensing device, formed as an injection molded component of thedispensing device, or in any other location within or without thedevice.

The dispensing device may employ one or more levels of interface fordifferent types of authorized users, for example the patient, the nurse,the physician, pharmacist or other authorized medical or healthcarepersonnel. These different interfaces may include components such askeypads, buttons, graphical icons and instructions, lights, LED's,monochrome or color graphical or text displays, touch-screens, LCD's,sounds, tactile feedback, voice recognition interfaces, and other inputand output devices and means. The activity, or mode, of the userinterface may be determined by the mode of operation of the dispensingdevice, by a login or access activity by a user such as a password orcode entry, by the connection or disconnection of the dispensing devicefrom a dock, computer, or network, or by the detection of an authorizedaccess key, such as a key, and/or RFID tag, or similar combination. Uponchanging the interface mode, the functionality of the device may bechanged, either activating, inactivating or changing the functionalityof the various interface components described above. By allowing thedevice to have one or more interface modes, with differing functionalityassociated with each one, the device can be optimized for various uses.

Base Station

In some embodiments the drug dispensing system includes a base stationfor recharging the drug dispensing device and the portable docking FOBbetween uses. This base station allows for recharging the batteries orfuel cells in multiple dispensing devices and/or FOBs simultaneously. Inaddition to recharging the drug dispensing devices and FOBs, the basestation may provide one or more of the following functionality: wirelessor wired connectivity to a peripheral device, computer or network;feedback on the charging state for the devices being recharges; aninterface for viewing, adding, deleting, or modifying the data on a drugdispensing device or FOB; a means for synchronizing data betweenmultiple drug dispensing devices and/or FOBs; and a means for conductinga diagnostic test on drug dispensing devices and/or FOBs.

VIII. Methods and Systems for Delivering Small Volume Dosage Forms Usinga Device

Exemplary features of the dispensing device include the following:

In one embodiment, the head, body, and cartridge comprise the handheldportion of the device. This device assembly has a latch to disconnectthe head and body, and a dispense button for patient use. The devicealso has lights to show lock-out status, errors, and power. In thisembodiment, the cartridge which contains the drug dosage forms and thebody are used a single time only.

The system may comprise a portable dock which is handheld, independentof the patient device and solely for healthcare professional use. Thedock enables higher level feature use such as deeper queries intopatient device use, the ability to upload device data, unlocking of thehead/body and the tether, lockout override for dosing the patient, and alarger reading display. The dock is also used to setup and take down thepatient device.

The system may also comprise an RFID bracelet that is activated via thedock and is worn by the patient to establish and control dosing tocorrect patient and to that patient alone. This feature prohibits use ofthe device by others.

The system may further comprise a recharging base used to charge thedock and heads and is also used to update the heads and docks when newsoftware becomes available or when new users are programmed into thesystem.

The drug dosage forms are typically provided in single use disposablecartridges which are loaded into the device prior to administration.

Exemplary set-up instructions for the device include the followingsteps:

The device head and dock are charged on the recharging station.

The device body and wristband are removed from the packaging.

The device head and dock are removed from the charging station.

The cartridge is loaded into the body by inserting a cartridge into thedevice body as indicated ensuring that the cartridge “clicks” and islocked in place.

The device body (with cartridge) is assembled onto the head.

The power button on the assembled device is pushed to power-up thesystem.

The power button on the dock is pushed to power-up the dock.

The assembled device is plugged into the dock.

A healthcare professional scans their fingerprint or inputs a uniquepassword in order to unlock the dock.

The device reads the label on the cartridge and the dock displays setupinformation, for example, the drug name, the quantity of tablets, thedrug concentration, the preset lockout time, the duration of use (72hours), and the battery status of the head.

After the information is read from the cartridge and displayed on thedock, the healthcare professional will be requested to confirm that allinformation is correct and will require a witness to verify theinformation.

The dock will require that the patient wristband be paired to the deviceby bringing the wristband close to the device.

The device will read the band and request confirmation of the bandnumber; selection and confirmation of the number

The patient ID is entered into the dock. i.e. patient medical recordnumber

The wristband is placed on the patient's hand that will be used tooperate device.

Then, the dock will indicate that it is ready to dispense a plasticinitialization tablet or “shipping tablet”.

Upon confirmation, the device will dispense a plastic initializationtablet or “shipping tablet”. This step is used by the device tocalibrate the dispensing mechanism, initiate the cartridge for use, andallows the healthcare professional to verify proper use and to train thepatient with a “shipping” or placebo-type tablet.

Once the plastic initialization tablet or “shipping tablet” isdispensed, the dock will require the healthcare professional to confirmthat the plastic tablet was dispensed.

After confirmation, the display will indicate that the device is readyfor use.

In some cases, a tether can be connected to the device via the dock. Thedock will allow the healthcare professional to lock and unlock thetether as required.

If a patient will self administer a drug dosage form using the device,the patient will be trained prior to use.

Exemplary use of the claimed devices and systems is provided in Examples6-8.

In one exemplary embodiment, the present invention provides a system,comprising: (1) a dispensing device for administration of a drug dosageform to the oral mucosa of a subject, for example, a small-volume dosageform or NanoTab®; (2) a dosage form for oral transmucosaladministration, such as a small-volume dosage form or NanoTab®; and (3)a subject.

In another exemplary embodiment, the system for administration of dosageforms to a patient using a drug dispensing device of the inventionincludes a drug dispensing device wherein the dispensing device includesa means for reducing or eliminating moisture and saliva ingress suchthat the drug dosage forms remain dry inside the device prior to andduring use.

Additional features which may be included in a system of the inventioninclude a docking station or other docking means, a means ofcommunication with a computer network such as a bidirectionalcommunication link with a local or remote computer system (wired orwireless), a pharmaceutical network monitoring and control apparatus, acomputer network that stores, records and transits information aboutdrug delivery from the device and one or more user interfaces.

In one approach, the computer network of the dosage form dispensingsystem of the present invention may comprise one or more of: a means tostore, record, receive, and transit information about drug delivery fromthe drug delivery device; an internal clock to track time and date, ameans to reset or modify memory, a non-invasive means to measurerespiratory rate, temperature, pulse rate, or blood pressure wherein theresults are stored and transmitted via the computer network; a means tochange the lock-out time of the drug delivery device or dispenser. Adocking station that finds utility in practicing the present inventionmay function to retrieve, store, communicate data to another device,peripheral, or computer, and/or recharge a battery. The system furthercomprises one or more user interfaces and a graphic display such as anLCD display.

Disposable and Reusable Drug Dispensing Devices of the Invention

When the desired use of the dispensing device of the invention has beencompleted, and the dispensing device is no longer needed, it may beeither fully disposable, partially disposable and partially reusable, orit may be fully reusable. In one exemplary application, the dispensingdevice may be used to place a sublingual tablet under the tongue of apatient, and then afford a means of locking the patient out fromself-administering another sublingual tablet until a safe lockout timehas elapsed between dosing, a means for recording the dosing history,and a means for communicating this history to a user, a computer,another electronic device, or a network.

Because many of the components of the dispensing device of the inventionare of high value, and the dispensing end may pose a contagious diseasehazard, it may be advantageous to dispose of the dispensing end andreuse the end containing the microprocessor, the memory means, battery,etc. A reusable dispensing device dispenser would require areplenishable power source, such as a rechargeable battery, replaceablebattery, refillable fuel cell, or other means of replenishing the systempower. The dispensing device may consist of any combination of thefollowing: fully disposable or reusable tip portion, fully disposable orreusable cartridge portion, fully disposable or reusable head portion,fully disposable or reusable head and tip combination, a fixed orportable dock for access and data transfer, a recharge station, adiagnostic station, and a keyed assembly and disassembly station.

In one exemplary embodiment the dispensing device for inpatient(hospital, clinic, etc.) use consists of a disposable tip portion, adisposable drug cartridge portion, and a reusable head portion. Thedisposable tip portion would contain the delivery tip, a dispensingmechanism, a means to connect and lock to a reusable head, and means toprevent saliva from entering beyond the tip. The disposable drugcartridge would contain a plurality of drug dosage forms, a means forbeing inserted into a reusable head or a disposable tip, and a means forordering and containing the dosage forms. The reusable head wouldcontain a microprocessor, a memory means, a power supply such as abattery, a user interface including buttons, a keypad, a display, andLED lights, a means to be recharged between uses and a means forallowing a disposable cartridge to be inserted into the head, a meansfor attaching and locking to a disposable tip. During setup when anauthorized user, e.g., a nurse, is preparing the dispensing device foruse by a patient, the nurse would open a new disposable tip from apackage, would obtain a new drug filled cartridge from the hospital drugdispensing system, and would obtain a recharged reusable head from arecharging station. The nurse would insert the drug cartridge into thereusable head or disposable tip, then would assemble and lock thedisposable tip to the reusable head, thus enclosing the disposable drugcartridge inside the assembled device. The nurse would then show thepatient how to use the device and give the device to the patient forself dosing. During disassembly, when the patient had completed histherapy with the dispensing device, the nurse would unlock the reusablehead from the disposable body, revealing the drug cartridge (container)within. The nurse would dispose of the drug cartridge and any remainingdrug in accordance with hospital protocols, dispose of the disposabletip in a sharps or biohazard container, and would wipe down the reusablehead with an antiseptic wipe, then place the head on a rechargingstation for recharging the battery and future reuse.

The present invention provides exemplary dispensing devices with asingulator dispensing mechanisms including a reusable single doseapplicator. The singulator dispensing mechanisms may include thefollowing; a reusable single dose applicator; a foil blister; rotatingstations; a disk with ejectors; a ribbon peeler; a ribbon picker; disksingulators; a flexible disk; an arc or helical type single doseapplicator; a pushrod stack ejector; and a rotating stack ejector.

The ability of the dispensing device to recognize a specific cartridgemay include mechanical, optical (e.g. bar code), electronic (e.g.microchip), magnetic, radio frequency, chemical, or other means ofdetecting and identifying the cartridge. In one exemplary embodiment ofthe invention, the cartridge may contain a physical keying detail on thecartridge that is physically detected by a sensor or switch or a seriesof sensors or switches in the dispensing device. When the cartridge isloaded into the dispensing device, the sensor or switch array can read amechanical key and identify the cartridge and its contents and/or otherinformation.

In another exemplary embodiment, the cartridge is manufactured with aunique electronic microchip and the dispensing device is equipped with amicrochip reader, such that upon loading of the cartridge into thedispensing device the dispensing device reads the information on themicrochip identifying the cartridge and its contents and/or otherinformation.

In some embodiments, the cartridge may be modified such that upon asuccessful or unsuccessful loading attempt into a dispensing device, thedispensing device passes information to the cartridge that it has beenloaded or a loading attempt was made. Such a system may include acartridge with a physical, electronic, optical, magnetic, chemical, orother means of recording information from the dispensing device to thecartridge.

Once the dispensing device has identified the cartridge, or attempted toidentify the cartridge, the dispensing device may alter itsfunctionality or cease its functionality based on this information. Forexample, if the device detects and identifies a cartridge that containsa sublingual opioid dosage form, of a specific strength and duration ofaction for the treatment of post operative pain, the dispensing devicemay institute a specific lockout protocol between doses, a specificpatient identification protocol, a dosage history recording protocol,and it may alter its user interface appropriately, among other things.

Furthermore, an identification or keying feature on a cartridge may bemodified in the event of drug access inside or outside of the dispensingdevice such that the dispensing device may identify that the cartridgehas been opened prior to loading into the dispensing device. In thisfashion the dispensing device may detect if a cartridge that is beingloaded has been tampered with or previously used.

The present invention provides exemplary architectures includingreusable options. The present invention provides exemplary architecturesincluding reusable options. The reusable device may be cleaned,recharged, reloaded, or have its memory cleared after treatment and beused again. The drug dosage dispenser of the invention may contain aplurality of components that are assembled such that one or morecomponents are reusable, to allow for reuse of expensive or high valuecomponents and reduce waste, and one or more components are disposable,to allow easy disposal of dirty or contaminated components, componentsthat pose a contagious disease hazard, or components that contain unusedor contaminated drug. In one such exemplary embodiment, a dispensersystem, a disposable drug dosage form cartridge would be loaded into adisposable delivery portion of a dispenser. A reusable portion of thedispenser would then be joined to the disposable portion in such amanner as to afford a tamper deterrent lock between the components. Thereusable portion of the dispenser would detect the proper assembly ofthe cartridge and disposable portion of the dispenser, confirming properassembly and allowing normal use of the dispenser to ensue. Improper orincomplete assembly would result in the reusable portion of thedispenser locking and displaying an error code or indication for errordiagnosis.

The assembly of two or more components of the dispenser may contain alocking mechanism to prevent or deter tampering or diversion of the drugwithin. The locking mechanism may be afforded by means of a solenoid, amotor, a piezo-electric actuator, a pneumatic or hydraulic actuator, ashape-memory actuator, a latch, a pin, a snap, a cam, a slider, alinkage, or any other mechanical or electromechanical means.Furthermore, the locking means may be locked or unlocked by means of aphysical key, a combination, an electronic key, a magnetic key, passcode, PIN, encrypted or unencrypted logic signal, a wireless signal,RFID, finger print identification, or other means of mechanical orelectromechanical unlocking of a lock.

After use of the dispenser, and upon disassembly, the reusable portionor portions, may be retained for future use, while the disposableportion or portions may be disposed of.

Methods and systems for delivering small volume dosage forms, e.g.sufentanil-containing dosage forms using a device are provided. FIG. 31provides a schematic architecture connection diagram illustrating thevarious components that may be included in a dispensing device or systemfor dispensing small volume drug dosage forms, including a device with aseparate head 280, body 282 and disposable drug dosage cartridge 48, aportable docking fob 296, Patient RFID 281 and a base station 292.

FIG. 32A is a schematic depiction of an exemplary architecture 278having a reusable head. The reusable option includes the following: areusable head 280, a body 282, and a recharge station 284. Thisembodiment 278 is comprised of the following: a reusable head 280containing a power supply 277, a microprocessor and printed circuitboard (PCB) 275, an actuator 273, a user interface 279, a useridentification means 281; a disposable body 282 containing a disposabledrug dosage cartridge 48; and a recharging station 284. In thisembodiment the reusable head 280 is lockably connected and disconnectedfrom a disposable body 284. After use, the disposable body 282, the drugdosage form, and the cartridge 48 are disposed of, while the reusablehead 280 is cleaned and docked in the recharge station 284 to rechargethe power supply. The power supply 277 may be a rechargeable orreplaceable battery, a fuel cell, or any other means of powering thedevice. The actuator 273 may be a motor, solenoid, linear actuator,piezo-electric actuator, shape memory actuator, hydraulic or pneumaticactuator or any other means of actuating a mechanism. The user interface279 may be include a graphical or numeric display, a keypad, buttons,switches, dials, sliders, lights, LED's, LCD's, speakers, microphones,buzzers, or any other means of communication to or from a user. The useridentification means 281 may be an RFID tag reader, a Wi-Fi system, afingerprint reader, a voice recognition system, an image or facialrecognition system, a local area network that communicates by way of thehuman body, a DNA recognition system, a retinal scanner, or any othermeans of identifying an individual user or patient. The drug dosagecartridge 48 may be a stack, disk, tape, single dose applicator, an maycontain a single dose or a plurality of doses. The PCB 275 may include aprocessor, a memory means, a power regulator, a recharge cycle, apatient identification means, graphic drivers, and any other componentsor systems to affect the performance of the dispenser device 278. Thedispensing mechanism may be contained in the disposable body 282 or inthe reusable head 280 or partially in both locations. The rechargestation 284 may recharge the power supply, may perform a diagnostic onthe reusable head 280, or may serve as an informational dock, eitherwired or wireless, to communicate between the dispenser device andanother device, computer or network.

FIG. 32B is a schematic depiction of an exemplary architecture 286having a reusable head 280 containing an actuator 273, a PCB 275, apower supply 277, and a user identification means 281, a disposable body290, containing a drug dosage cartridge and drug dosage forms 48, adocking station 292 containing a communication means and user interface279, and a recharge station 284. The reusable option includes thefollowing: the reusable head 280, a disposable body 282, docking station284, and the docking station 292.

FIG. 32C is a schematic depiction of an exemplary architecture 294having a disposable body containing an actuator 273, a PCB 275, a powersupply 277, a user identification means 281, and a drug dosage cartridgecontaining drug dosage forms 48, a portable docking fob 296 containing auser interface 279, and a recharge station 284. The reusable optionincludes the following: a disposable body 282 with the portable dockingfob 296, and a recharge station 284 for recharging the fob.

FIG. 32D is a schematic depiction of an exemplary architecture 302having a disposable body 282 with dockability. The reusable optionincludes the following: a disposable body 282 containing an actuator273, a PCB 275, a power supply 277, a user identification means 281, anda drug dosage cartridge with drug dosage forms 48, and a docking station292 containing a user interface 279. The reusable option includes thefollowing: disposable body with a docking station.

FIG. 32E is a schematic depiction of an exemplary architecture 308having a reusable head 280 containing a power supply 277, amicroprocessor and printed circuit board (PCB) 275, an actuator 273, anda user identification means 281, a disposable body containing a drugdosage cartridge with drug dosage forms 48, a portable docking fob 296containing a user interface 279, and a recharge station for the head andfob. The reusable option includes the following: the reusable head 280with the fob 296, a disposable body 282, and a recharge station 284.

In one embodiment, the present invention further provides a fullydisposable device. The device is one-piece incorporating all componentsnecessary for drug dispensing and disposable after use, including apower supply 277, a microprocessor and printed circuit board (PCB) 275,an actuator 273, and a user identification means 281, a drug dosagecartridge with drug dosage forms 48, and a user interface 279. FIG. 32Fis a schematic depiction of an exemplary architecture 318, wherein afully disposable body 282 is shown.

The present invention further provides a dispensing device with alocking feature including movable push rod; non-returning push rod;electromechanical regulator; optical sensor pair; magnetic clutch;lockout on actuator; rack and pinion; safety button latch; solenoid;collet on shaft; keyed hubs; coupling; and cams.

FIG. 33 is a schematic depiction of the functional elements of the drugdispensing system 326, including a drug dispensing device andpharmaceutical network with a monitoring and control apparatus coupledvia a wireless or other bi-directional communication network. The system326 includes a battery 342 controlled microprocessor 352 which comprisesRAM 330 and ROM 332, is operably connected to a docking connector 344,and communicates in a bi-directional manner with an RFID antenna 336, aWI/FI antenna 338, wherein the drug dispensing device and pharmaceuticalnetwork further comprises, a user interface 328, an audible alarm 350, agraphic display 348, a dispensing button 346, dispensing sensor 340, anda dispensing button lockout 344. The device or dispensing device of thepresent invention may have a bidirectional communication link with alocal or remote computer system, wherein the computer system provides asignal that allows the device to dispense a small-volume drug deliverydosage form. The drug delivery device can store and dispense many dosesof a small, oral transmucosal drug formulation. The device/system 326includes a memory means such as RAM 330 and/or ROM 332, the microprocessor 352 or a central processing unit (CPU) for processinginformation and controlling various functional elements of the device326 and a battery 342, the docking connector 334 that can allow thedevice 326 to connect to another device, peripheral, or computer toretrieve, store, communicate data to the another device, peripheral, orcomputer, and recharge the battery 342, the RFID Antenna 336 or otherunique tag that allows easy identification of each individual device326, the Wi/Fi Antenna 338 that allows information be communicatedbi-directionally via a wireless system, a dispensing sensor 340 locatedon the exit port to detect the successful dispensing of a dosage form.In some embodiments, the drug dispensing system 326 can include a tethersensor, and/or a head/body assembly sensor.

FIG. 34A is a block diagram illustrating a system communication diagram354, comprising an RFID tag 356, a dispensing device 358, a basestation/dock 360 and a healthcare provider personal computer 362. Thedrug dispensing device 358 may communicate with the physician or caregiver, via the dock 360, by means of a wired or wireless communicationmethod to provide usage information and information regarding therespiratory status or blood pressure of the patient to the physician atregular intervals.

FIG. 34B is a block diagram illustrating a system communication diagram364, comprising an RFID tag 356, a dispensing device 358, a fob 366 anda healthcare provider personal computer 362. The drug dispensing device358 may communicate with the physician or care giver, via the fob 366,by means of a wired or wireless communication method to provide usageinformation and information regarding the respiratory status or bloodpressure of the patient to the physician at regular intervals. The fob366 can be adapted to attach to a cord so as to allow the fob 366 tohang from the neck of the physician or caregiver. This would help avoidmisplacing the fob 366 or theft of the fob 366, such as in the hospitalsetting.

The present invention provides a drug dispensing system including a drugdispensing device and a detecting means for detecting the identity of apatient. The dispensing system may further include a computer, a dockingstation, an access control means, and small volume drug dosage forms.The system further comprises a docking station, wherein the dockingstation is electrically connected to a computer network and informationis transmitted from the drug delivery device or dispensing device to thecomputer network. The computer network is wireless and information istransmitted from the drug delivery device or dispensing device to thecomputer network via the wireless network. The computer network stores,records and transits information about drug delivery from the drugdelivery device. The system may further comprise a non-invasive means tomeasure respiratory rate, pulse rate, temperature or blood pressurewherein the results of the measurements are stored and transmitted viathe computer network. In one embodiment, the system further comprises ameans to change the lock-out time of the drug delivery device. Inanother embodiment, the system may comprise a drug delivery device withan antagonist reservoir that allows the antagonist and drug to combinein the event of a system or power failure, device damage or tampering.In addition, a means that uses a sensor to detect blood chemistry,breath chemistry, saliva chemistry and on the like is also provided

Further embodiments of the device include the ability to storehistorical use information and the ability of the device to communicatewith another device or computer to transmit such information. Forexample, such a bidirectional exchange of information may beaccomplished by downloading stored information to a computer through aphysically wired interface, such as a USB or any other communicationconnection. Alternatively, information may be communicated via awireless system. Such information may include historical useinformation, for example the number of dosages stored and dispensed, andthe times of dispensing.

In certain embodiments, the device includes a docking station that mayquery the device, reset it between dosing, lock it when not properlyaccessed, and control the dosing regimen. The drug dispensing device maycommunicate with a physician or care giver, via the dock, by means of awired or wireless communication method to provide usage information andinformation regarding the respiratory status, blood pressure or otherbiometric measurement of the patient's status to the physician atregular intervals. The dispensing device may lock out at regularintervals or time periods, e.g., each day or week or two weeks,requiring the patient to dock the dispensing device and communicate withthe physician or care giver to unlock the device for the next fixedperiod. In this way the device and dock enable greater physicianoversight and care management.

In other embodiments, the docking station may load single or multipledoses into the device each time it is docked and properly accessed.

In certain embodiments, the device may be adapted to receive a cartridgeof individually packaged single dose applicators each containing asingle dose of the drug.

A drug dosage dispenser of the invention may be used to administer adrug dosage forms that is sensitive to moisture and/or humidity. In suchcases, there is a need for a drug dosage form cartridge that protectsthe drug dosage form from humidity, moisture, saliva, mucus, etc. Thecartridge may be cylindrical, disk-shaped, helical, rectilinear,non-ordered, or may take the form of any assemblage of drug dosage formsthat allows the dispenser to dispense them in a controlled manner. Toprevent the unused drug dosage forms from absorbing moisture orotherwise becoming exposed to moisture prior to use, the cartridge mayprovide a means of sealing the drug dosage forms from exposure tomoisture. This may accomplished by use of a cartridge that containsindividually packaged drug dosage forms separated by a thin impermeablefoil or impermeable material such that when one drug dosage form isdispensed from the cartridge, the seal protecting the remaining dosageforms remains unbroken. Alternatively, the dosage forms may be packagedin such a manner within the cartridge that two or more dosage forms arepackaged together in each separate sealed compartment. In someembodiments, all of the dosage forms in a cartridge may be packagedtogether in a foil sealed compartment.

The drug dosage form cartridge may afford a seal against moisture bymeans of a septum, an elastomeric seal or valve, a sliding, translating,hinged door or valve, or by means of sealing against another componentof the dispenser when loaded. In this manner, a single re-sealable sealmay be opened either independently or by means of the passage of adosage out of the cartridge. Once the dosage form is delivered from thecartridge, the re-sealable seal on the cartridge may be re-sealed toprevent moisture or other contaminants from damaging the remaining drugdosage forms within the cartridge. The cartridge may further have anon-re-sealable seal that is broken when it is loaded into the dispenseror upon delivery of the first dosage form from the cartridge.

In other embodiments, the cartridge contains a desiccant or otherabsorbent or adsorbent material to absorb or adsorb moisture thatpenetrates the cartridge either prior to use or during normal use. Acartridge for use in a dispensing device of the invention may containany combination of individually sealed dosage forms, multiply sealeddosage forms, re-sealable seals, non-re-sealable seals, desiccants,absorbents, or adsorbents.

In one exemplary embodiment a stack of solid tablet dosage forms ispackaged in a cylindrical cartridge with a sliding seal at the distalend and a spring pre-loading the tablets toward this distal end. Whenthe drug cartridge is loaded into the dispenser, the sliding sealremains in place, protecting the drugs within the cartridge frommoisture and humidity. Upon dispensing of a dosage form, the slidingseal slides out of the way, allowing the spring to advance the stack sothat a single tablet dosage form is dispensed. Once this tablet isdispensed, the sliding seal moves back into place to continue to sealthe remaining tablets from moisture and humidity.

In a second exemplary embodiment, a stack of solid tablet dosage formsis packaged in a cylindrical cartridge with a foil seal at the distalend, a spring pre-loading the tablets toward this distal end, and asealing surface that will seal against a component internal to thedispenser once it is loaded into the dispenser. When the cartridge isloaded into the dispenser, the foil seal is broken, and the distal endof the cartridge seals against a component of the dispenser so as toprotect the tablet dosage forms from humidity and moisture. When atablet is dispensed, a component of the dispenser that provides a sealto the cartridge is moved out of the way, allowing a single dosage formto be dispensed. Once the dosage form is dispensed, the dispenserre-seals the cartridge, protecting the remaining dosage forms frommoisture and humidity.

In a third exemplary embodiment, a disk shaped cartridge with individualspaces for individual solid tablet dosage forms arranged around theperiphery of the disk is loaded with solid tablet dosage forms andsealed on both faces with a metal foil to protect the tablets frommoisture and humidity. When loaded into the dispenser and when a dosageform is dispensed, push rod breaks through the foil on one face at thelocation of one of the individual compartments, contacting the tabletdosage form, and pushing it through the second seal on the opposite faceof the disk cartridge, breaking through the second foil, and dispensingthe tablet. In this manner, only a single tablet is dispensed, and theseals for the remaining tablets remain intact, protecting them frommoisture and humidity. After the dispensing of the tablet, the diskindexes one location so that the next compartment containing the nexttablet is in position to be dispensed next, for example, as shown anddescribed with reference to FIGS. 15A and 15B.

Methods of Use of a Drug Dispensing Device of the Invention for OralTransmucosal Drug Delivery

Delivery of a single dosage form using a drug dispensing device of theinvention may be accomplished as detailed in the figures describedbelow.

FIG. 35 is a block diagram illustrating a dispensing device programmingflow chart 372, wherein the process involves the steps of: loading adosage form cartridge into the dispensing device. If loading issuccessful 374, the process goes to the next step. If unsuccessful 376,the process goes back to the first step of loading a dosage formcartridge into the dispensing device; closing and locking the dispensingdevice. If successful 378, the process goes to the next step. Ifunsuccessful 380, the process goes back to the previous step of closingand locking the dispensing device; docking the dispensing device intothe PC. If successful 382, the process goes to the next step. Ifunsuccessful 384, the process goes back to the previous step;programming the dispensing device. If successful 386, the process goesto the next step. If unsuccessful 388, the process goes back to theprevious step; recording a thumbprint or PIN to identify the appropriateuser. If successful 390, the process goes to the next step. Ifunsuccessful 392, the process goes back to the previous step; andtesting the dispensing device if a dispensing works properly. Ifsuccessful 396, the programming ends 398. If unsuccessful 394, theprocess goes back to the first step to correct the programming.

FIG. 36 is a block diagram illustrating a dispensing device operationflow chart 400, wherein an example of stepwise operation of a drugdispensing device of the invention is provided. The detailed stepsinclude: pressing any button to wake-up the dispensing device 402. Theuser verifies if a preprogrammed lock-out time is over. If thepreprogrammed lock-out time is not over yet, the user goes back to theprior step of waking up the dispensing device and repeats the process.If the verification is satisfied, the dispensing device is unlocked fordispensing a drug dosage form. Inputting patient identification 404using e.g., a thumbprint, or PIN verification, is performed. If patientidentification 404 is incorrect 408, it results in lock-down of thedevice 426. If the patient identification 404 is correct 406, theprocess goes to the next step: detecting an RFID tag 410. If incorrect414, it results in lock-down of the drug dispensing device 426. Ifdetecting an RFID tag is successful 412, the user proceeds to the nextstep by which the user verifies if a lock-out device is not blockingdelivery and dispensing is fine. Then a comparison is made of the (a)dispensing request, (b) dispensing history, and (c) programmedprescription 416. If (a), (b) and (c) are consistent with permission todispense a dosage form from the drug dispensing device of the invention,dispensing is ready 418. If not ready, lock-down of the dispensingdevice is resulted in 420. Displaying dispensing device status and IDwhich indicates the drug dispensing device is ready 422. Dispensing adosage form when the dispense button is pressed 424. The dispensingdevice begins to dispense the drug dosage form to a patient. Uponcompletion of dispensing the dosage form, the dispensing device lock-outis locked down for a preprogrammed period 426. The steps are repeatedfor a future dispensing of the drug dosage form.

FIG. 37 is a block diagram illustrating another exemplary dispensingdevice operation flow chart 428, wherein an example of stepwiseoperation of a drug dispensing device of the invention is provided. Themethod comprises the following steps: a user may press any button towake-up the dispensing device 430. Then the device verifies if apreprogrammed lock-out time, such as 10 min, is over. If thepreprogrammed lock-out time is over, patient identification isattempted, i.e. using 432, detecting an RFID tag is performed. If thepreprogrammed lock-out time is not over yet 434, the user goes back tothe prior step of waking up the dispensing device and repeats theprocess. If detecting an RFID tag is successful 436, the device proceedsto the next step and verifies that it is the mechanical dispensing is infunctional condition. If detecting an RFID tag is unsuccessful 438, theuser goes back to the first step. If the verification is satisfied 440,the dispensing device is unlocked for dispensing a drug dosage form. Ifthe verification is not satisfied 442, an error message indicating afailure of the mechanical check is prompted 444. If the mechanical checkis ok, then the motor-driven dispensing of a drug dosage form to apatient is performed. Upon completion of dispensing, the dosage form,the dispensing device lock-out is locked down for a preprogrammedperiod. The steps are repeated for a future dispensing of the dosageform 446.

In another example of the process of dispensing drug dosage forms usinga drug delivery device of the present invention, the process includesthe steps of: (1) load; (2) check; (3) position; and (4) deliver. Thisprocess comprises the following steps: (1) loading the drug dispensingdevice with a plurality of drug dosage forms; (2) checking the deliverystatus and verifying, for example, by a green light indicating that thelock-out mechanism is not blocking delivery and the device is armed witha drug dosage form; (3) positioning the device to deliver a dosage formof the invention under the tongue of the appropriate patient; and (4)delivering the dosage form to the patient by activating the device. Thered light or other indicator is always visible when the device is notready for delivery. The drug dispensing information is communicated tohealth care personnel such that the dosing regimen is adjusted to ensurethat the patient is receiving the appropriate drug dose at theappropriate frequency to provide therapeutic efficacy.

FIG. 38 is a block diagram illustrating another exemplary dispenseroperation flow chart 448, wherein an example of stepwise operation of adrug dispensing device of the invention is provided. The methodcomprises the following steps: a user presses any button to wake-up andunlock the dispenser 452 in sleep mode 450. Then the user verifies if apreprogrammed lock-out time, such as 10 min, is over. The preprogrammedlock-out time is over 454, the system verifies that the user isauthorized for access, such as detecting a user identity (e.g. an RFIDtag, fingerprint, etc.), is performed 458. If the preprogrammed lock-outtime has not expired 456, the system returns to the first step of wakingup the dispenser and repeats the process. If the user identity isdetected and authorized 458, the system proceeds to the next step inwhich the system is unlocked for delivery 462. If the user identity isnot detected or not authorized 460, the system returns to the first stepof waking up the dispenser and repeats the process. Once the system isunlocked, it remains unlocked for 5 seconds before re-locking 464. Ifthe user presses the second button before the 5 seconds has elapsed 466,the button will dispense a dosage form 468. Once the dispensing iscompleted, the system is locked 470 until the next dispensing attempt ismade. The steps are repeated for a future dispensing of the dosage form472.

FIG. 39 is a block diagram illustrating an exemplary dispenserdisassembly flow chart by a healthcare professional 474, wherein anexample of stepwise disassembly of a drug dispensing device of theinvention is provided. As exemplified in FIG. 39, a healthcareprofessional may disassemble and dispose of the dispenser in a secure,controlled manner.

FIG. 40 is a block diagram illustrating an exemplary outpatient acutedispensing device operation flow chart 518, wherein an example ofstepwise operation of a drug dispensing device of the invention isprovided. FIG. 40 depicts a stepwise operation of an exemplaryoutpatient acute dispensing device.

FIG. 41 is a block diagram illustrating an exemplary inpatient dispenserassembly and preparation flow chart 550, wherein an example of stepwiseassembly and preparation of a drug dispensing device of the invention isprovided. FIG. 41 depicts a stepwise assembly and preparation of theinpatient dispenser.

FIG. 42 is a block diagram illustrating an exemplary outpatient chronicdispensing device operation flow chart 598, wherein an example ofstepwise operation of a drug dispensing device of the invention isprovided. FIG. 42 depicts a stepwise operation of the outpatient chronicdispensing device.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention belongs. Although any methods, devicesand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, the preferred methods,devices and materials are now described.

IX. In Vivo Human Studies

Provided herein is pharmacokinetic data obtained in animals and humansbased on studies where sufentanil and alfentanil were administered viathe sublingual route using the claimed small volume dosage forms.

A human clinical study was performed using healthy volunteers. The studywhich is detailed in Example 1 below was performed with 12 subjects (6men and 6 women) using sublingual sufentanil dosage forms containingeither 2.5 mcg, 5 mcg or 10 mcg of sufentanil base corresponding to 3.7mcg, 7.5 mcg or 15 mcg of sufentanil citrate, respectively (see Table1). All excipients were “pharmaceutically acceptable” (inactive and haveGRAS or “generally recognized as safe” status.

Sufentanil dosage forms designed for sublingual use were compared to IVsufentanil, administered through an IV catheter as a continuous infusionover 10 minutes. Plasma samples were drawn from a different IV catheterat a remote location. The assay demonstrated good inter-day precisionand accuracy at the high, medium and low quality control sampleconcentrations.

The dosage forms for this study eroded over a period of 10-30 minutes inall subjects. After placement of each sufentanil dosage form in thesublingual cavity of the 12 healthy volunteers, a remarkably consistentpharmacokinetic profile was obtained (see FIG. 43 and Table 2). Thebioavailability compared to IV administration for single administrationof all three dosages averaged 91%, which is far superior to thatmeasured for commercially available fentanyl transmucosal preparations,Actiq and Fentora (47% and 65%, respectively—Fentora package insert).Although this high bioavailability could be due to a number of factorsincluding but not limited to erosion time, it is likely that the lack ofsaliva produced by the small size of the dosage forms limits theswallowing of the drug and avoids the low bioavailability typical ofdrug absorption via the GI route. Both Fentora and Actiq package insertsclaim at least 50% and 75% of the drug dose, respectively, is swallowedvia the saliva, and both exhibit lower bioavailability than the claimeddosage forms.

The dosage forms used in this clinical trial had a volume ofapproximately 5 microliters (mass of 5.5-5.85 mg), a small fraction ofthe size of Actiq or Fentora lozenges. The dog studies described inExample 4 demonstrate that sufentanil has very poor GI bioavailability(12%), therefore, given the high bioavailability of the sufentanildosage forms, wherein drug is administered by the oral transmucosalroute, the data supports the conclusion that greater than 75% of thedrug is absorbed transmucosally. Therefore, less than 25% of the drug isswallowed, which is a much lower percentage than is swallowed withFentora or Actiq.

Importantly, this bioavailability is also linked to the consistency oftotal drug delivered to the patient. For example, the total plasma drugarea under the curve (AUC O-infinity) for sufentanil dosage forms 10 mcgwas 0.0705±0.0194 hr*ng/ml (mean±standard deviation (SD)). This SD isonly 27.5% of the total AUC. Coefficient of variation (CV) is a term todescribe the percent SD of the mean. The coefficient of variation forthe fentanyl products, Fentora (AUC is 45%) and Actiq (AUC is 41%;Fentora package insert), while the coefficient of variation for theclaimed sublingual sufentanil dosage forms is less than 40%. Therefore,the total dose delivered to the subject is not only more bioavailablefor the sufentanil dosage forms but it is more consistent.

The sufentanil sublingual dosage forms are also superior in terms ofconsistent drug plasma levels early after administration. The C_(max)obtained with the 10 mcg sufentanil dosage form was 27.5±7.7 pg/ml. Thecoefficient of variation of the C_(max) is therefore only 28%. TheC_(max) for Fentora and Actiq suffer from variability of GI uptake ofdrug. Fentora reports a C_(max) of 1.02±0.42 ng/ml, therefore thecoefficient of variation of the C_(max) is 41%. The range ofcoefficients of variation for the various doses of Fentora is from 41%to 56% (package insert). Actiq coefficient of variation of C_(max) isreported as 33% (Fentora package insert).

In addition to superior bioavailability and consistency in plasmaconcentrations, the time to C_(max), also referred to as T_(max), isimportant since quick and consistent onset of pain relief is importantin the treatment of acute pain. The T_(max) for 10 mcg sufentanil dosageforms was 40.8±13.2 minutes (range 19.8-60 minutes). The reportedaverage T_(max) for Fentora is 46.8 with a range of 20-240 minutes. TheT_(max) for Actiq is 90.8 minutes, range 35-240 minutes (Fentora packageinsert). Therefore, the consistency in onset of analgesia for sufentanildosage forms is markedly improved over Fentora and Actiq, with a 400%decrease in the slowest onset of T_(max).

Important in the treatment of acute pain, especially acute breakthroughpain, is a consistent and relatively short half-life of the drug. Theplasma elimination half-life of the 10 mcg sufentanil dosage form was1.71±0.4 hours, which allows the drug to be titratable for variouslevels of pain. If the breakthrough pain event lasts longer than 1.5hours then the patient can dose with another dosage form. The plasmaelimination half-life of Actiq and Fentora are 3.2 hours and 2.63 hours,respectively, for the lowest doses. The half-lives for the higher dosesincrease substantially for these drugs, thereby limiting thetitratability of these drugs.

Although still in development, published data allows comparison of thesufentanil pharmacokinetic data provided herein to that of Rapinyl, afentanyl sublingual fast-dissolve lozenge. As previously mentioned, theobserved bioavailability for the claimed sufentanil dosage averaged 91%as compared to the published bioavailability for Rapinyl which isapproximately 70% (Bredenberg, New Concepts in Administration of Drugsin Tablet Form, Acta Universitatis Upsaliensis, Uppsala, 2003). Thecoefficient of variation of the AUC (0-infinity) for Rapinyl ranges from25-42% depending on dose, whereas the coefficient of variation for theclaimed 10 mcg sufentanil dosage forms is 27.5%. This highbioavailability would suggest that regardless of dose, the sufentanildosage forms have a consistently low coefficient of variation of AUC,whereas this is not true for Rapinyl. In fact, the coefficient ofvariation around the AUC for all three doses of sufentanil exemplifiedherein (2, 5, and 10 mcg) averaged 28.6%, demonstrating that theobserved low coefficient of variation is not dependent on dose.

The coefficient of variation of the C_(max) for Rapinyl varies from34-58% depending on dose. As shown by the data presented herein,administration of the 10 mcg sufentanil dosage form resulted in aC_(max) variation of only 28%, and the average coefficient of variationof C_(max) for the 2, 5, and 10 mcg doses was 29.4%, indicating minimalvariability depending on dose. Similarly, the coefficient of variationfor T_(max) with Rapinyl ranges from 43-54% depending on dose, whereasfor our sufentanil dosage forms, this coefficient of variation forT_(max) averages only 29% over all three dosage strengths. Thisconsistent onset of action achieved with sublingual sufentanil dosageforms allows a safer redosing window when compared to any of the threecomparator drugs, since rising plasma levels are contained to a shorterperiod.

Additionally, as with Fentora and Actiq, Rapinyl demonstrates a longerplasma elimination half-life (5.4-6.3 hours, depending on dose) than theclaimed sufentanil dosage forms. The plasma elimination half-life ofsufentanil dosage forms ranged from 1.5-2 hours following a single oraltransmucosal administration in humans (Table 2), which allows for moretitratability and avoids overdosing. As will be understood by those ofskill in the art, the half-life described herein for the exemplifieddosage forms may be adjusted by modification of the component andrelative amounts of the excipients in the formulation used to make agiven dosage form. The ability to titrate to higher plasma levels byadministering repetitive doses of the sublingual sufentanil dosage formswas also tested in this human study.

Repeat dosing of 5 mcg dosage forms every 10 minutes for four dosingsresulted in a bioavailability of 96%, indicating that repetitive dosingto achieve higher plasma levels while still maintaining highbioavailability is possible. Whether treating post-operative pain orcancer break-through pain, being able to efficiently titrate to anindividual's own level of pain relief is important.

Another aspect of the PK curves generated by sublingual sufentanildosage forms is the plateau phase, which allows for a period ofconsistent plasma levels, which is important for both safety andefficacy. Compared to either IV bolus administration (see Animal StudiesExamples 2-5) or the 10 minute IV infusion in our human study (Example 1and FIG. 43), the PK profile for the sufentanil dosage forms is clearlysafer. Rapid, high C_(max) plasma levels are avoided. Given the abilityof opioids to produce respiratory depression, avoiding these high peaksin the PK profile is advantageous.

An important mathematical ratio that demonstrates the prolonged plateauphase of the measured blood plasma levels of sufentanil followingadministration of a dosage form is the time spent above 50% of C_(max)divided by the known IV terminal elimination half-life of the drug:

${{Therapeutic}\mspace{14mu}{Time}\mspace{14mu}{Ratio}} = \frac{{{Time}\mspace{14mu}{of}\mspace{14mu}{offset}\frac{C_{\max}}{2}} - {{Time}\mspace{14mu}{of}\mspace{14mu}{onset}\mspace{14mu}{of}\frac{C_{\max}}{2}}}{{IV}\mspace{14mu}{Elimination}\mspace{14mu}{Half}\text{-}{Life}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{Drug}}$

The elimination half-life is an intrinsic property of the molecule andis measured most reliably using the IV route to avoid contamination fromcontinued uptake of drug from the sublingual route. The IV eliminationhalf-life for 5 mcg of sufentanil in our human study was 71.4 minutesdue to the detection limits of the assay at these low doses. Thepublished IV elimination half-life for sufentanil at much higher dosesis 148 minutes, due to detection of both the rapid alpha-eliminationmechanism of redistribution and the longer beta phase of elimination viametabolism and excretion. This published elimination half-life is moreaccurate and more appropriate to use in the above equation. The timespent above 50% of C_(max) on average for the 12 volunteers for the 2.5,5 and 10 mcg dosage strengths was 110 minutes, 111 minutes and 106minutes, respectively. Therefore, the Therapeutic Time Ratio for thesespecific sufentanil dosage forms ranged from 0.72-0.75. As theformulation of the dosage forms is varied, erosion time of the dosageform will be either decreased or increased, and one might see a range ofTherapeutic Time Ratios from approximately 0.2-2.0 for sufentanil.

The Therapeutic Time Ratio is a measure of how successfully short-actingdrugs are formulated to produce an increase in therapeutic time andincrease safety by avoiding high peak plasma C_(max) concentrations. Forexample, as a comparison, the sufentanil IV arm of the human studydemonstrated a Therapeutic Time Ratio of 10 min/148 min=0.067. This lowratio value for the IV arm, therefore, is a measure of the high peakproduced by IV infusion of sufentanil and demonstrates that thisformulation does not produce a significant plateau phase. There is a10-fold higher Therapeutic Time Ratio for the sufentanil formulationslisted in Table 1 (the dosages used in the human study) versus IVsufentanil, indicating a prolonged therapeutic plateau profile for theseformulations.

The uptake of transmucosal medications via small volume drug dosageforms results in a more consistent drug delivery between individualdosages and individual patients as compared to that of currentlyavailable oral transmucosal dosage forms for which a large fraction ofdrug uptake occurs via the GI route.

The methods and systems described herein are designed to workeffectively in the unique environment of the oral cavity, providing forhigher levels of drug absorption and pain relief than currentlyavailable systems. The claimed methods and systems are designed to avoidthe high peak plasma levels of intravenous administration by entry intothe circulation via the sublingual mucosa.

The claimed methods and systems further provide for independent controlof bioadhesion, dosage form disintegration (erosion) and drugdissolution and release over time, together with administration using adevice to provide a safe delivery profile. The device-administered oraltransmucosal dosage forms provide individual, repetitive doses thatinclude a defined amount of the active agent (e.g., sufentanil), therebyallowing the patient or care giver to accurately titrate the amount ofdrug delivered and to adjust the amount as appropriate in a safe andeffective manner. The lock-out feature of the dispensing device adds tothe safety of the drug delivery profile.

An advantage of the oral transmucosal dosage forms herein is that theyexhibit high consistent bioavailability and can maintain the plasma drugconcentration within a targeted therapeutic window with significantlylower variability for a longer duration than currently availablemedications or systems for treatment of pain. The high peak plasmalevels typically observed for IV dosage forms are blunted followingadministration of sufentanil-counting dosage forms. In addition, a rapiddecline in plasma levels is avoided since the drug is continuallycrossing from the oral cavity into the bloodstream during the length oftime of erosion of the dosage form or longer, thus providing plasmapharmacokinetics with an extended plateau phase as compared to the IVroute of administration. Further, treatment with the claimed methods andsystems provides for improved safety by minimizing the potentiallydeleterious side effects of the peaks and troughs in the plasma drugpharmacokinetics, which are typical of currently available medicationsor systems for treatment of pain.

Advantages of the claimed sublingual dosage forms over various liquidforms for either sublingual or intranasal administration include localrelease of drug from the dosage form over time with minimal swallowingof liquid drug via either the nasal or oral/GI route. Publishedpharmacokinetic data following administration of intranasal sufentanilliquid (15 mcg) in humans demonstrates a bioavailability of 78% (Helmerset al., Canadian Journal of Anaesthesia 36:494-497, 1989). Sublingualliquid sufentanil administration (5 mcg) in Beagle dogs (see Example 4below) resulted in a bioavailability of 40%. The aforementionedbioavailability data are less than the 91% average bioavailability thatwas obtained in human volunteers using sufentanil administeredsublingually in the form of a small volume dosage form (see Example 1below).

Due to the small size of the oral transmucosal dosage forms, repeatedplacement in the sublingual cavity over time is possible. Minimal salivaproduction and minimal physical discomfort occurs due to the small size,which allows for repetitive dosing over days to weeks to months. Giventhe lipid profile of the sublingual cavity, the sublingual route, alsoallows for slower release into the plasma for certain drugs, such assufentanil, which may be due to utilization of a “depot” effect thatfurther stabilizes plasma levels compared to buccal delivery.

The oral transmucosal dosage forms are designed to fit comfortably underthe tongue such that the drug form erodes sufficiently slowly to avoidthe immediate peak plasma levels followed by significant drop off seenin prior art formulations such as described in U.S. Pat. No. 6,759,059(Rapinyl), wherein fentanyl was administered via tablets containing 400mcg of fentanyl which resulted in a peak plasma level of 2.5 ng/mlfollowed by an immediate drop in plasma level. Fentora (fentanyl buccaltablet) also suffers from a lack of a plateau phase but rather has asteep incline up to the C_(max) followed by a significant drop-off inplasma levels (Fentora package insert).

Animal Studies

A series of studies in awake, alert Beagle dogs was performed to morefully elucidate the properties of small volume oral transmucosal dosageforms using various drugs and formulations. A comparison of the claimedsystem for oral transmucosal administration of sufentanil relative toadministration of liquid sublingual sufentanil or swallowed sufentanildosage forms was made to evaluate various attributes of the drug dosageforms. The results support the claim that the small, volume drug dosageforms of the invention are well tolerated sublingually (as demonstratedby use in awake dogs) and result in higher bioavailability and moreconsistent pharmacokinetic data than other oral transmucosal dosageforms, including instilled liquids.

The first Beagle dog study was carried out to compare a sublingual 5 mcgsufentanil dosage form to IV sufentanil as described more fully inExample 2 below. A total of three Beagle dogs were studied and theresults are graphed in FIG. 44 and tabulated in Table 3. Thebioavailability of the sublingual sufentanil dosage forms was 75%compared to IV. Therefore, similar to the human data, thisbioavailability data in dogs confirms the superior attributes of thedosage forms over larger dosage forms. Furthermore, similar to the humandata, the coefficient of variation for the AUC was low, 14%, compared tothe variation of other commercial transmucosal dosage forms. TheTherapeutic Time Ratio of the sublingual sufentanil dosage forms is 0.28whereas the Ratio for IV sufentanil is 0.05 (using the published IVelimination half-life of sufentanil in dogs of 139 minutes). Therefore,similar to humans, the 5 mcg dosage form in Table 1 resulted in a muchhigher Therapeutic Time Ratio (5.6-fold) compared to IV sufentanil indogs.

Additional studies determined the effect of varying the formulation onthe pharmacokinetic profile. This study is explained more fully inExample 3 below. By prolonging the erosion time of the dosage form, theplasma half-life was extended from 33 minutes for the mediumdisintegrating formulation (in Example 2) to 205 minutes. TheTherapeutic Time Ratio was increased from 0.28 to 1.13 for the slowdisintegrating dosage forms. This study illustrates the flexibility ofthe small volume dosage forms, and the ability based on excipientselection, to alter the PK of the drug. This flexibility is possible dueto the small size of the dosage forms, which allows either short orprolonged contact time with the sublingual mucosa without dislodging orcreating excess saliva which would prematurely wash the drug into the GItract.

Another study in Beagle dogs was performed to evaluate the advantages ofthe sublingual dosage form over liquid administration sublingually. Thisstudy is described more fully in Example 4 below. The results indicatethat although delivery of sufentanil (5 mcg) in an instilled liquid formto the sublingual cavity results in rapid T_(max), this method of drugadministration results in very low bioavailability (40%) compared tosublingual sufentanil dosage forms (75%). This is probably due toswallowing of the liquid drug. Moreover, the AUC is extremely variable,as shown by the high coefficient of variation (82%). The C_(max) is alsohighly variable with this method of drug administration, demonstrating acoefficient of variation of 72%. The Therapeutic Time Ratio forinstilled liquid sufentanil sublingually was calculated as 0.06, verysimilar to the IV sufentanil arm for this study which demonstrated aRatio of 0.03. Therefore, this instilled sublingual liquid profile doesnot provide the advantageous therapeutic plateau observed with thesublingual dosage forms. These findings support that the high sublingualbioavailability observed from different formulations is not intrinsic tothe molecule but rather it is a direct result of the unique design ofthe dosage form and its formulation. The strong adherence of the smalldosage forms to the oral mucosa in the sublingual cavity minimizes thevariability in the surface area available for absorption, as is the caseof a liquid solution, thus improving delivery of the molecule to thesystemic circulation. In addition, owing to its unique design and smalldimensions, the dosage forms do not elicit significant salivaproduction, thus reducing the potential for ingestion of the releaseddrug. Both factors contribute to the higher and more uniform drugabsorption from the sublingual cavity.

An additional part of this study in Example 4 was the determination ofthe bioavailability of swallowed sufentanil dosage forms. Since there islittle to no data on sufentanil GI bioavailability in the literature, itwas important to further evaluate the low bioavailability of this routeof administration to further support the observation that drug from thesublingual dosage forms could not be swallowed and maintain a highbioavailability. As indicated by the PK analysis data in Table 7, oralbioavailability of sufentanil from the swallowed dosage forms is verylow, approximately 12%. In addition, as predicted from the known erraticGI uptake of fentanyl, the swallowed dosage forms demonstrated extremelyhigh variability both in the amount of drug absorbed (AUC) and thepharmacokinetics of absorption (C_(max), T_(max)) as shown in Table 7.These data support the conclusion that bioadhesive sublingual dosageforms strongly adhere in the sublingual cavity in such a manner thatthey don't dislodge, thus avoiding oral ingestion and avoiding the highvariability of plasma levels which is typical when drug is absorbed viathe GI route.

Additional studies evaluating alfentanil, formulated into small volumedosage forms were performed in Beagle dogs and are more fully describedin Example 5 below.

Alfentanil dosage forms resulted in a bioavailability of 94% compared toIV alfentanil and a coefficient of variation of 5% for the AUC, 7% forC_(max) and 28% for T_(max). The Therapeutic Time Ratio was calculatedas 0.33, compared to 0.04 for the IV alfentanil arm of this study(calculated using a published IV elimination half-life of 104 min foralfentanil in dogs). Therefore, the alfentanil formulation (as describedin Example 5) produces an 8-fold improved Therapeutic Time Ratio overthe IV alfentanil arm. The high bioavailability of this formulationagain supports the claim that minimal swallowing of drug occurs with useof the dosage forms.

X. Utility of Small-Volume Oral Transmucosal Dosage Forms

The claimed dosage forms find utility in delivery of any drug that canbe administered by the oral transmucosal route. The small volume of theoral transmucosal dosage forms is that they provide for highbioavailability, low variability in T_(max), low variability in C_(max)and low variability in AUC. The dosage forms also provide for prolongedplasma levels within the therapeutic window.

In one exemplary embodiment described in detail herein, the dosage formsfind utility in treating a subject suffering from pain that may beassociated with any of a variety of identifiable or unidentifiableetiologies. In this embodiment, the dosage forms find utility insuppression or mitigation of pain. The term “treatment” or “management”of pain is used here to generally describe regression, suppression, ormitigation of pain so as to make the subject more comfortable, asdetermined for example by pain score.

The invention finds utility in the treatment of both opioid naivepatients and opioid tolerant patients.

The term “opioid naive patient” is used herein with reference to apatient who has not received repeated administration of an opioidsubstance over a period of weeks to months.

The term “opioid tolerant patient” as used herein means a physiologicalstate characterized by a decrease in the effects of an opioid substance(e.g., analgesia, nausea or sedation) with chronic administration. Anopioid substance is a drug, hormone, or other chemical substance thathas analgesic, sedative and/or narcotic effects similar to thosecontaining opium or its derivatives. If analgesic tolerance develops,the dose of opioid substance is increased to result in the same level ofanalgesia. This tolerance may not extend to side effects and sideeffects may not be well tolerated as the dose is increased.

The dosage forms find particular utility in the treatment of acute painor other conditions “in the field”, i.e., under highly sub-optimalconditions. Paramedics or military medics often are required to treatsevere acute pain or other injuries or conditions in non-sterilesituations, where needles used for IV or IM administration can result inunintended needle sticks, risk of infection, etc. Oral opioid tabletsoften take 60 minutes to provide relief which is too long for someone insevere pain. The claimed dosage forms find utility in addressing thisneed.

When the dosage forms are used for the treatment of pain, the claimedmethods and systems find utility in administration of drugs to pediatricand adult populations and in treatment of human and non-human mammals,as well as in opioid tolerant and opioid naive patient populations.

Application of the claimed methods and systems is not limited to anyparticular therapeutic indication. As such, the claimed dosage formsfind utility in administration of drugs to pediatric and adultpopulations and in the treatment of human and non-human mammals.

The dosage forms find utility in pediatric applications, since thecomfortable and secure nature of the dosage form allows children toreadily accept this mode of therapy and will reliably deliver drugtransmucosally. Specific examples include, but are not limited to,treatment of pediatric acute pain when IV access is not available orinconvenient, treatment of pediatric asthma when the child is not ableto use an inhaled route of administration effectively, treatment ofnausea when a child can not or will not swallow a pill, pre-proceduralsedation when a child is NPO (no oral intake allowed) or a more rapidonset is required.

The dosage forms find further utility in veterinary applications.Specific examples include, but are not limited to, any treatment of anacute condition for which IV administration is not readily available orinconvenient, such as pain relief, anxiety/stress relief, pre-proceduralsedation, etc.

The following examples are provided to illustrate the invention and arenot intended to limit any aspect of the invention as set forth above orin the claims below.

The dosage forms for the dosage forms described above can be tested forin vivo drug pharmacokinetics in both humans and a suitable animal modelfollowing sublingual administration.

The following examples demonstrate the ability of the dosage forms toallow a consistent absorption profile of sufentanil citrate followingsublingual administration in human volunteers and awake, alert Beagledog model.

Example 1 Sublingual Sufentanil Dosage Forms Administered Sublinguallyin Adult Human Volunteers

TABLE 1 Sufentanil Formulations Used in the Human Clinical Study #46 #47#47 2.5 μg Sufentanil Base 5.0 μg Sufentanil Base 5.0 μg Sufentanil Base% % % Mass Mass Mass Mass Mass Mass in Mass in in Mass in in in Mass inin in Batch tablet, tablet, Batch tablet, tablet, Batch tablet, tablet,Ingredient (g) mg w/w (g) mg w/w (g) mg w/w Sufentanil 0.3750 0.003750.068 0.75 0.0075 0.068 1.5000 0.0150 0.273 Citrate Mannitol 406.604.066 79.931 406.30 4.063 79.931 405.500 4.055 73.727 200SD Poloxamer 110.110 2.000 11 0.110 2.000 11 0.110 2.000 (Lutrol F68) Polyox 16.5 0.1653.000 16.5 0.165 3.000 16.5 0.165 3.000 WSR 303 PEG-8000 82.5 0.82515.001 82.5 0.825 14.999 82.5 0.825 15.000 Stearic Acid 27.5 0.275 5.00027.5 0.275 5.000 27.5 0.275 5.000 Mg Stearate 5.5 0.055 1.000 5.5 0.0551.000 5.5 0.055 1.000 Total 549.975 5.49975 100 550.050 5.005 100550.000 5.5 100 Calculated 0.002506159 0.005012 0.0100255? Strength(Sufentanil base)

A human clinical study was performed using healthy volunteers. The studywas performed with 12 subjects (6 men and 6 women) using Sufentanildosage forms (formulations #46-#48 shown in Table 1) manufactured tohave a volume of 5 μL, a mass of approximately 5.5 mg, and determined tohave a uniform size for all dosage strengths with dimensions ofapproximately 3 mm in diameter and 0.8 mm in thickness. Sufentanildosage forms contained either 2.5 mcg, 5 mcg or 10 mcg of sufentanilbase corresponding to 3.7 mcg, 7.5 mcg or 15 mcg of sufentanil citrate,respectively. All excipients were inactive and have GRAS (“generallyrecognized as safe”) status. The sufentanil dosage forms were tested forsublingual use. Study staff administered individual dosage forms to asubject by placing them directly at the base of the frenulum usingblunt-tipped forceps.

For bioavailability calculations, intravenous sufentanil, 5 mcg wasdiluted in 0.9% saline to a total volume of 20 mL, and was administeredthrough an IV catheter as a continuous infusion over 10 minutes. Plasmasamples were drawn from a different IV catheter at a remote location.This human trial was a cross-over design with wash-out periods betweentransitions from higher to lower doses. Subjects were blocked with theopioid antagonist naltrexone daily to avoid opioid-induced side-effects.Day 0: IV sufentanil Infusion: Seventeen samples were collected: −5.0(before the start of infusion), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45,60, 90, 120, 160, 320, 480 and 640 minutes Day 2: sublingual 2.5 mcgsufentanil dosage forms; Seventeen samples: −5.0 (before dosage formadministration), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120,160, 320, 480 and 640 minutes Day 3: sublingual 5.0 mcg sufentanildosage forms; Seventeen samples: −5.0 (before dosage formadministration), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120,160, 320, 480 and 640 minutes Day 4: sublingual 10.0 mcg sufentanildosage forms; Seventeen samples: −5.0 (before dosage formadministration), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120,160, 320, 480 and 640 minutes Day 7: sublingual 5.0 mcg sufentanildosage forms repeated 4 times at 10 minute intervals; Twenty threesamples: −5.0 (before the first dosage form administration), 5, 7.5minutes 10 (immediately prior to the second dosage form administration),15, 17.5 minutes 20 (immediately prior to the third dosage formadministration), 25, 27.5 minutes 30 (immediately prior to the fourthdosage form administration), 35, 40, 45, 50, 55, 60, 90, 120, 150, 190,350, 510 and 670 minutes

The total volume of blood required for pharmacokinetic sampling wasapproximately 455 mL.

Sufentanil concentrations in plasma samples were determined using avalidated LC-MS/MS sufentanil human plasma assay. The assay demonstratedgood inter-day precision and accuracy at the high, medium and lowquality control sample concentrations.

The dosage forms for this study eroded over a period of 10-30 minutes inall subjects. After placement of each sufentanil sublingual dosage formsin the sublingual cavity of the 12 healthy volunteers, a remarkablyconsistent pharmacokinetic profile was obtained for the three dosages(FIG. 43).

TABLE 2 PK Analyses of the IV (5 mcg) and Sublingual Sufentanil DosingArms in the Human Clinical Study using Three Dosage Strengths (2.5 mcg =#46, 5 mcg = #47, 10 mcg = #48) Plasma AUC Absorption Elimination (hr *ng/ml) Variability C_(max) Half-life Therapeutic Group (mean ± SD) F (%)(% CV) (pg/mL) T_(max) (min) (hr) Time Ratio¹ Intravenous 0.0368 ±0.0076 — 20.7 0.0813 ± 0.0281 9.6 ± 1.8 1.19 ± 0.18 0.067 SufentanilSublingual 0.0178 ± 0.0044 97.8 24.7 0.0068 ± 0.0021 43.8 ± 7.8  1.65 ±0.43 0.74 Sufentanil dosage form (Formulation #46) Sublingual  0.273 ±0.0093 76.7 34.1 0.0109 ± 0.0035 46.2 ± 17.4 1.54 ± 0.57 0.75 Sufentanildosage form (Formulation #47) Sublingual 0.0705 ± 0.0194 98.2 27.50.0275 ± 0.0077 40.8 ± 13.2 1.71 ± 0.40 0.75 Sufentanil dosage form(Formulation #48) Repeat Dosing 0.1403 ± 0.0361 96.4 25.7 0 0464 ±0.0124 62.4 ± 13.8 1.97 ± 0.30 NA of #47 Sufentanil dosage form every 10min. x 4 ¹Represents the relative time that the drug achievestherapeutic levels (above 50% of C_(max)) and is calculated by theformula: TTR = (Time spent above 50% of C_(max))/(IV Terminalelimination half-life). The denominator is obtained from literature andis 148 min in humans for sufentanil.

Example 2 In Vivo Evaluation of Sublingual Sufentanil Dosage Forms in aDog Model

The following Examples 2-5 are using the Beagle dog model and theformulations for the dosage forms all are using a dosage form with atotal mass of 5.5 mg. The in vivo pharmacokinetics (PK) of sufentanilfollowing sublingual administration of the 5 mcg dosage forms(formulation #44 for dogs, which is the same as the human formulation#47) described above were evaluated in a healthy Beagle dog model.Briefly, single 5 mcg dosage forms described above were administeredsublingually in fully awake healthy dogs by direct placement in thesublingual cavity. A total of three dogs were evaluated. Followingadministration, the position of the dosage form in the sublingual cavitywas observed visually at 5-15 minute intervals following administration.The sublingual sufentanil PK was compared with that of IV administeredsufentanil at the same dose level.

All dogs were catheterized via the cephalic vein for blood collectionsup to 2 hours post-dosing. Through the 2-hour post-dose bloodcollection, all dogs were fitted with an Elizabethan collar to preventremoval of the catheter. The catheter was removed following the 2-hourblood collection. The 4-, 8-, and 24-hour post-dose blood collectionwere collected from the cephalic or other suitable vein. Approximately 2ml of blood were collected into pre-chilled tubes containing potassiumEDTA at the following time points: prior to dosing and approximately 1,3, 5, 10, 15, min, 1, 2, 4, 8 and 24 hours post-dose. The samples wereanalyzed with the appropriately validated LC/MS/MS method for thedetermination of sufentanil citrate in dog plasma. The sufentanil plasmaconcentrations and the pharmacokinetic results are shown in FIG. 44 andTable 3.

TABLE 3 PK Analyses of the IV (5 mcg) and Sublingual Sufentanil DosingArms in Beagle Dogs. Plasma AUC Absorption Elimination Therapeutic (hr *ng/ml) Variability C_(max) T_(max) Half-life Time Group (mean ± SD) F(%) (% CV) (pg/mL) (min) (min) Ratio¹ Intravenous 211.5 ± 48.2 — 22.8536.7 ± 186.1  1.6 ± 0.6 10.3 ± 4.5 0.05 ± 0.02 Sufentanil SublingualSufentanil 161.2 ± 23.1 74.8 ± 10.7 14.3 222.7 ± 25.9  11.7 ± 2.5 33.3 ±5.8 0.28 ± 0.16 dosage form (Formulation # 44) ¹Represents the relativetime that the drug achieves therapeutic levels (above 50% of C_(max))and is calculated by the formula: TTR = (Time spent above 50% ofC_(max))/(IV Terminal elimination half-life). The denominator isobtained from literature and is 139 min in beagle dogs for sufentanil.

Example 3 Exemplary Sufentanil Dosage Forms to Control Drug Release andIn Vivo Pharmacokinetics

For purposes of illustration, a longer duration dosage form (formulation#58) was prepared with sufentanil citrate in order to evaluate a slowerrate of drug release and in vivo pharmacokinetics of a longer-actingdosage form. This slower disintegrating sufentanil dosage form, asdescribed in Table 4 was prepared by direct compression and tested asdescribed above. The range of erosion times in dogs was 35-120 minutesand the bioadhesion of the placebo formulation was measured as describedabove and determined to be 0.18±0.08 N/cm².

Sample analysis was performed using a validated LC/MS/MS method foranalysis of sufentanil in dog plasma. Pharmacokinetic analysis wasperformed using a non-compartmental model of absorption. The results ofa limited PK analysis are shown in Table 5.

TABLE 4 Slow Disintegrating Sufentanil Formulation CompositionFormulation #58 Sufentanil citrate 0.5456 Mannitol 40.3 Carbopol 97120.00 PEG 8000 25.60 HPMC 10.00 Polyox 303 2.60 Mg Stearate 1.00 Total100.00

TABLE 5 PK Analyses for the Slow-Disintegrating Sublingual SufentanilDosage Form in Beagle Dogs. Plasma Elimination Therapeutic GroupHalf-life (min) Time Ratio¹ Sublingual formulation #58 205 ± 93.1 1.13 ±0.69 ¹Represents the relative time that the drug achieves therapeuticlevels (above 50% of C_(max)) and is calculated by the formula: TTR =(Time spent above 50% of C_(max))/(IV Terminal elimination half-life).The denominator is obtained from literature and is 139 min in beagledogs for sufentanil.

Example 4 In Vivo Study of Sublingual Sufentanil Solution and Swallowingof Sufentanil Dosage Forms in a Dog Model

A. Evaluation of Bioavailability of Sufentanil Following SublingualAdministration of a Solution Dosage Form

The bioavailability of sufentanil following sublingual administrationfrom a solution as compared to that intravenously was evaluated in ahealthy, conscious Beagle dog animal model, as indicated in Table 6. Inboth arms of the study the commercially available formulation ofsufentanil citrate (Sufenta® 50 μg/mL) was used and was dosed at thesame total dose of 5 mcg of sufentanil base. Intravenous administrations(Group 1) were performed by single administration (n=3) of Sufenta® 50μg/mL by bolus injection to the cephalic vein via a sterile needle andsyringe of appropriate size. For the sublingual administrations (Group2) the test article was prepared by appropriately diluting Sufenta® 50μg/mL with 0.9% w/w to the same final dose of 5 mcg of sufentanil baseand was administered twice sublingually (n=6 total), with each doseseparated by a minimum of a 2-day washout. Doses were slowly appliedunder the tongue, adjacent to the frenulum via a sterile syringe. Bloodsamples were collected from a jugular or other suitable vein prior todosing and approximately 1, 3, 5, 10, 15, 30 min, 1, 2, 4, 8 and 24hours post-dose. Approximately 2 mL of blood were collected pertime-point into pre-chilled tubes containing K₂ EDTA. The samples werecentrifuged at 3,000·times·g for approximately 10 minutes in arefrigerated centrifuge. Plasma was collected and frozen within 20minutes of centrifugation at approximately −70° C. and was maintained atthe same temperature until analysis. Sample analysis was performed usinga validated LC/MS/MS method for analysis of sufentanil in dog plasma.

Pharmacokinetic analysis was performed using a non-compartmental modelof absorption. The sufentanil plasma concentrations are graphed in FIG.45. The results of the PK analysis are shown in Table 7.

B. Evaluation of Bioavailability of Sufentanil Following Oral Ingestionof a Dosage Form

The bioavailability of sufentanil following ingestion of a 5 mcgsufentanil dosage form (formulation #44, which is the same formulationas #47 used in the human study above) as compared to intravenoussufentanil administration was evaluated in a healthy, conscious Beagledog animal model, as described in the previous example. A single 5 mcgdosage form was administered twice orally, with each dose separated by aminimum of a 2-day washout for a total of n=6 (Table 6). The dosageforms were placed manually as far back as possible in the throat andflushed with water to promote the swallow response in the animal.Pharmacokinetic analysis was performed using a non-compartmental modelof absorption. The sufentanil plasma concentrations are shown graphed inFIG. 45. The results of the PK analysis are shown in Table 7.

TABLE 6 Organization of Test Groups Dose Level Route of Number of TotalNumber of Group Treatment (μg)^(a) Administration animals^(b) Animals, n1 Sufentanil solution 5.0 IV 3 3 2 Sufentanil solution 5.0 Sublingual 3^(c) 6 3 Ingested Sufentanil 5.0 Oral  3^(c) 6 dosage form ^(a) =expressed as free base. ^(b) = Same animals will be used for Groups 1through 3 with a minimum 2-day washout period between dosing. ^(c) =Groups 2 & 3 animals were dosed twice with a minimum 2-day washoutperiod for a total of n = 6 ^(d) = Normal (0.9% w/w saline) was used todilute the test article (Sufenta ® 50 μg/mL) to the desiredconcentration.

TABLE 7 PK Analyses of Intravenously Administered Sufentanil Compared toa Sublingually Instilled Sufentanil Solution and an Ingested SufentanilDosage Form in Beagle Dogs. Plasma AUC Absorption Elimination (mean ±Variability T_(max) C_(max) Half-life Therapeutic Group SD) F (%) (% CV)(min) (pg/mL) (min) Time Ratio¹ Intravenous 123.3 ± 49.3 — 21.8  1.0 ±0.0 536.7 ± 186.1 2.8 ± 0.4 0.02 ± 0.0  Sufentanil Sublingual  58.3 ±36.4 40.0 ± 32.7 81.8  4.3 ± 1.0 236.4 ± 170.0 8.3 ± 4.5 0.04 ± 0.02Sufentanil solution Ingested dosage  15.9 ± 22.4 12.2 ± 15.3 134.2 14.6± 9.9 33.8 ± 33.2 22.5 ± 16.8 0.13 ± 0.09 form ¹Represents the relativetime that the drug achieves therapeutic levels (above 50% of C_(max))and is calculated by the formula: TTR = (Time spent above 50% ofC_(max))/(IV Terminal elimination half-life). The denominator isobtained from literature and is 139 min in beagle dogs for sufentanil.

Example 5 In Vivo Evaluation of Sublingual Alfentanil HCl Dosage Formsin a Dog Model

For purposes of illustration of another drug use for the dosage form, anadditional dosage form was prepared with alfentanil HCl in order todemonstrate the ability of the dosage forms described in thisapplication to effectively improve the PK of alfentanil compared to thatof the IV route of administration. The formulation composition, a mediumdisintegrating dosage form, is described in Table 8. The erosion time indogs of formulation #63 was 20 minutes and the bioadhesion was measuredat 0.056±0.01 N/cm² for the placebo formulation.

The dosing parameters for this study are shown in Table 9. Thealfentanil plasma concentrations are graphed in FIG. 46. PK analysis wasperformed using a non-compartmental absorption model. The results of thePK analysis are shown in Table 10. Blood sampling and storage mirroredthe conditions described earlier; sample analysis was performed using avalidated LC/MS/MS method for analysis of alfentanil in dog plasma.

TABLE 8 Exemplary Alfentanil Dosage Form Formulation #63 % compositionAlfentanil HCl 5.00 Mannitol 52.00 Carbopol 974 7.00 PEG 8000 35.00 MgStearate 1.00 Total 100.00

TABLE 9 Dosing Parameters for Administration of Sublingual AlfentanilDosage Forms and an Intravenous Alfentanil Solution in Beagle Dogs. DoseLevel Route of Number of animals Group Treatment (μg)^(a) Administration(Males) 1 Alfentanil solution 253.0 IV 3 2 Alfentanil dosage 239.0 ±16.2 Sublingual 2 form ^(a) = expressed as free base. ^(b) = Sameanimals were used for Groups 1 and 2 with a minimum 2-day washout periodbetween dosing.

TABLE 10 PK Analyses of Alfentanil Sublingual Dosage Forms compared toIntravenous Alfentanil in Beagle Dogs. Plasma AUC Absorption Half-Therapeutic (hr * ng/ml) Variability T_(max) C_(max) life Time Group(mean ± SD) F (%) (% CV) (min) (pg/mL) (min) Ratio¹ Intravenous 15.3 ±1.6 — 10.5  1 ± 0 139.1 ± 76.4  4.4 ± 2.4 0.04 ± 0.02 AlfentanilSublingual 14.4 ± 0.7 94.1 ± 4.6 4.9 15.0 ± 4.2 35.5 ± 2.6 40.8 ± 8.50.33 ± 0.07 Alfentanil dosage form ¹Represents the relative time thatthe drug achieves therapeutic levels (above 50% of C_(max)) and iscalculated by the formula: TTR = (Time spent above 50% of C_(max))/(IVTerminal elimination half-life). The denominator is obtained fromliterature and is 104 min. in beagle dogs.

Example 6 Acute Pain Management in the Outpatient Setting byAdministering a Sufentanil-Containing Dosage Form Using a Device

A pharmacist loads a drug dispensing device with a drug cartridge whichincludes 40 sufentanil dosage forms. Each cartridge has two coloredinitialization tablets (called “shipping tablets”) arranged to be thefirst two tablets dispensed. The device has a means for loading thecartridge, which is either a port, hatch, or door that is secure andinaccessible to unauthorized users. Once the pharmacist has loaded thecartridge into the device, he locks the device access port, hatch ordoor. The pharmacist then docks the dispensing device for the first timeto a dock that is connected to a personal or other computer, using thedocking connector, and then programs the device. Programming involvesuploading the dosage strength of the dosage forms, the number of dosageforms loaded in the device, the prescribed frequency of dosage formusage, the number of dosage forms to be used per day, the current dateand time, the preferred language, a valid thumbprint or otheridentification for identifying the patient, and the physician'sidentification information, in case the device is lost and found.

Once the dispensing device is programmed, the pharmacist demonstratesproper usage and tests the device by dispensing a single shippingtablet. The pharmacist then gives the dispensing device to the patientand observes the patient dispense a shipping tablet to ensure properusage and functionality. Along with the dispensing device, thepharmacist provides the patient with a radio frequency identification(RFID) tag that must be within approximately 5 inches of the device toallow the dispensing device to operate.

When the patient wants to administer a dose of the drug, he or she willhold the dispensing device, and push any button to wake the device upfrom its sleep mode. The device will query the user for either athumbprint reading or a personal identification number (PIN). The devicewill then search for a validated RFID key within range. Once theseconditions are met, the dispensing device will query its internal memoryand clock to make sure that the dosage regimen programmed by thepharmacist is not being violated by the current usage request. At thispoint the device displays status information, such as the date and time,the number of doses left, the last time a dosage was used, the patient'sname, etc., and the pharmacist informs the patient that the device isready to dispense the dosage forms by a visual and/or audible signal.

The patient will hold the dispensing end of the device under his or hertongue and press the dispensing lever. When the dosage form is dispenseda tone will sound to inform the patient that the dosage form wasproperly delivered. At this point the device will lock down to preventfurther dispensing until the preprogrammed lock-out time has passed, atwhich time the device will be ready to use again.

Example 7 Acute Pain Management in the Inpatient Setting byAdministering a Sufentanil-Containing Dosage Form Using a Device

A post operative patient requires acute pain treatment followingsurgery. The surgeon prescribes oral transmucosal sufentanil to beadministered using the drug dispensing device. The attending nurse takesthe prescription order to the pharmacist or automated pharmaceuticalinventory management system (e.g. Pyxis) and obtains asufentanil-containing drug cartridge for sublingual delivery. Thecartridge is labeled and equipped with an RFID electronic tag containingdrug label information. The cartridge is labeled and equipped with anRFID electronic tag containing drug label information.

The nurse then takes a disposable dispensing portion of the drugdispensing device from inventory, and proceeds to a base station toobtain a reusable controller portion of the drug dispensing device thathas completed its recharge cycle and is ready for use. The nurse insertsthe drug cartridge into the disposable dispensing portion, and thenaffixes this to the reusable controller portion of the drug dispensingdevice and locks the disposable portion into the reusable portion of thedrug dispensing device. At this point the device reads the RFID tag onthe drug cartridge and uploads the appropriate drug information,including the type of drug, the dosage strength, the programmed lockoutperiod between doses, etc. The nurse confirms the proper drug cartridgeinformation has been read by the drug dispensing device and gives thedrug dispensing device to the patient for patient controlled dispensingof the pain medication.

When the patient requires pain medication, she takes the drug dispensingdevice in her hand, and places the dispensing tip in her mouth, underher tongue and presses the dispense button. The drug dispensing devicethen does an internal check to ensure that the proper lockout period haselapsed since the last dosage dispense. At this point the drugdispensing device dispenses a dosage form under the patient's tongue andprovides feedback that dosing was successful. The patient removes thedrug dispensing device from her mouth and allows the sublingual dosageform to dissolve under her tongue. The patient may attempt to dispenseas frequently as she desires, but the drug dispensing device will onlyallow successful dosing after the appropriate lockout period haselapsed. The drug dispensing device electronically logs the dispensingattempts and successful dispenses in its dosing history.

Periodically the nurse checks on the patient and drug dispensing device.During such checks, the nurse inspects the drug dispensing device to seethat there are no errors and to check the number of remaining dosageforms in the drug dispensing device, and returns it to the patient.

When the patient is discharged, the nurse takes the drug dispensingdevice and unlocks the reusable portion from the disposable portion,disposes of the cartridge and disposable portion of the drug dispensingdevice. The nurse then connects the reusable portion of the device to acomputer and uploads the patient use information from the drugdispensing device to the computer for input into the patient's medicalrecords. The nurse cleans the reusable controller portion and returns itto the base station for recharging.

Example 8 Acute Pain Management in the Inpatient Setting byAdministering a Sufentanil-Containing Dosage Form Using a Device and aPortable Dock

A post operative patient requires acute pain treatment followingsurgery. The surgeon prescribes oral transmucosal sufentanil to beadministered using the drug dispensing device. The attending nurse takesthe prescription order to the pharmacist or automated pharmaceuticalinventory management system (e.g. Pyxis) and obtains asufentanil-containing drug cartridge for sublingual delivery. Thecartridge is labeled and equipped with an RFID electronic tag containingdrug label information. The cartridge is labeled and equipped with anRFID electronic tag containing drug label information. The cartridgeincludes a shipping tablet or initialization tablet in the first to bedispensed location of the dosage form stack.

The nurse then takes a disposable dispensing portion of the drugdispensing device from inventory, and proceeds to a base station toobtain a reusable controller portion of the drug dispensing device thathas completed its recharge cycle and is ready for use. The nurse insertsthe drug cartridge into the disposable dispensing portion, and thenaffixes this to the reusable controller portion of the drug dispensingdevice. Next, the nurse takes a portable dock (or docking fob) from thebase station where it has been recharging, and docks the assembled drugdispensing device to the portable dock. The portable dock and theassembled drug dispensing device communicate electronically and a setupmenu comes up on the portable dock for setting up the drug dispensingdevice.

At this point the device locks the reusable and disposable portionstogether, reads the RFID-tag on the drug cartridge and uploads theappropriate drug information, including the type of drug, the dosagestrength, the lockout period between doses, etc. The dispensing devicewrites a code to the RFID tag on the cartridge identifying it as a usedcartridge. The nurse enters her fingerprint in the fingerprint reader onthe portable dock to gain secured access and proceeds to set up the drugdispensing device for use. The set up procedure includes enteringpatient identification, the nurse's identification, confirming theproper time on the device, and confirming the proper drug cartridgeinformation. The nurse then takes a disposable RFID bracelet and placesthis adjacent to the drug dispensing device at which point the drugdispensing device reads the tag and the nurse confirms that the properbracelet tag has been read.

The nurse then confirms proper setup of the drug dispensing device bypressing the dispensing button once. The drug dispensing deviceactuates, dispensing the shipping tablet facsimile into the nurses hand,confirming proper operation. The drug dispensing device detects thedispensing of the shipping tablet, allowing for an internal system checkof proper operation and internal calibration of the newly assembledsystem. If the internal dispensing check is successful, the portabledock queries the nurse to confirm that the shipping table was properlydispensed, and the nurse confirms the proper setup. The nurse thendisengages the drug dispensing device from the portable dock, andproceeds to the patient's bedside for the final steps of setup.

The nurse places the RFID bracelet on the patient's wrist and affixes atheft resistant tether to the patient's bed and the other end to thedrug dispensing device. The nurse then instructs the patient on properuse of the sublingual drug dispensing device, and gives the drugdispensing device to the patient for patient controlled dispensing ofsufentanil.

When the patient requires pain medication, she takes the drug dispensingdevice in her hand, and places the dispensing tip in her mouth, underher tongue and presses the dispensing button. The drug dispensing devicethen does an internal check to ensure that the proper lockout period haselapsed since the last dosage dispense, and that the patient's RFIDbracelet is present and readable. At this point the drug dispensingdevice dispenses a dosage form under the patient's tongue and provides afeedback that dosing was successful. The patient removes the drugdispensing device from her mouth and allows the sublingual dosage formto dissolve under her tongue. The patient may attempt to dispense asfrequently as she desires, but the drug dispensing device will onlyallow successful dosing after the appropriate lockout period haselapsed. The drug dispensing device electronically logs the dispensingattempts and successful dispenses in its dosing history.

Periodically the nurse checks on the patient and device. During such apatient check in the nurse brings a portable docking FOB and docks thedevice to the FOB. The electronic connection enables the nurse todownload the information from the drug dispensing device to the fob.This information includes the use history, drug information, number ofremaining dosage forms and duration of use since initial set up. Thenurse then enters her fingerprint in the finger print scanner to gainaccess to the information and to drug dispensing device. Because thepatient is requiring an additional dose of drug prior to the lockoutperiod expiring, the nurse overrides the lockout period and then returnsthe drug dispensing device to the patient at which point the patient isable to take another dose.

The nurse leaves the patient's room with the portable docking FOB andreturns to the nurse's station to record the dosing history in thepatient's records. When finished the nurse returns the FOB to the basestation for recharging.

When the patient has used all of the dosage forms in the drug dispensingdevice, the nurse brings the portable docking fob into the patient'sroom and docks the drug dispensing device to the FOB. The nurse thenenters her fingerprint in the fingerprint scanner on the fob to gainsecured access to the drug dispensing device. Next, the nurse unlocksthe security tether and disconnects the drug dispensing device from thebed. She then unlocks the drug dispensing device and removes it from thefob for disassembly. The nurse disconnects the disposable portion fromthe reusable portion, and removes the cartridge from the disposableportion. The nurse disposes of the disposable portion and the cartridge,and wipes the reusable controller portion with an antiseptic wipe toclean it before returning it to the base station. The reusablecontroller portion requires that the nurse return it to the base stationwhere it recharges and runs an internal diagnostic test before beingready for use again.

The nurse then proceeds to set up a new drug dispensing device asdescribed above and provides this to the patient.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practiced. Various aspects ofthe invention have been achieved by a series of experiments, some ofwhich are described by way of the following non-limiting examples.Therefore, the description and examples should not be construed aslimiting the scope of the invention, which is delineated by the appendeddescription of exemplary embodiments.

The invention claimed is:
 1. An apparatus, comprising: a delivery tipdefining a non-linear delivery passage, a distal end portion of thedelivery tip defining an exit port; a push rod, at least a portion ofthe push rod being movably disposed in the delivery passage, a distalend portion of the push rod being within the delivery passage when thepush rod is in a first position, the distal end portion of the push rodconfigured to deliver a drug-containing tablet through the exit portwhen the push rod is moved from its first position to a second position;a shroud coupled to the distal end portion of the delivery tip, at leasta portion of the shroud configured to be disposed within a mouth of apatient between a tongue and a sublingual membrane and to inhibitcontact by at least one of the tongue or the sublingual membrane withthe exit port, the shroud including a hydrophilic material; and a sealdisposed about the exit port, the seal configured to prevent the ingressof moisture into the exit port, a portion of the seal defining a slitconfigured to permit passage of the tablet and the distal end portion ofthe push rod therethrough during delivery of the tablet, the portion ofthe seal configured to maintain a seal about at least one of the tabletor the push rod when the push rod is moved from its first position toits second position to deliver the tablet.
 2. The apparatus of claim 1,wherein the push rod is flexible.
 3. The apparatus of claim 1, whereinthe distal end portion of the push rod defines an opening therethrough,the apparatus further comprising: a sensor configured to detect thepassing of the opening when the push rod is moved within the deliverypassage.
 4. The apparatus of claim 1, wherein the distal end portion ofthe push rod defines an opening therethrough, the apparatus furthercomprising: an optical sensor assembly having a first portion and asecond portion, the optical sensor assembly configured to detect thepassing of the opening when the push rod is moved within the deliverypassage between the first portion and the second portion.
 5. Theapparatus of claim 1, further comprising: a sensor configured to detecta position of the push rod when the push rod is moved within thedelivery passage.
 6. The apparatus of claim 1, further comprising: asensor configured to distinguish the passing of a shipping tablet withinthe delivery passage from the drug-containing tablet within the deliverypassage.
 7. The apparatus of claim 1, wherein the shroud substantiallysurrounds the exit port.
 8. The apparatus of claim 1, wherein the sealis configured to maintain contact with at least one of the tablet or thepush rod when the push rod is moved from its first position to itssecond position to deliver the tablet.
 9. The apparatus of claim 1,wherein a shape of the slit defined by the seal substantiallycorresponds to a shape of at least one of the tablet or the push rod.10. The apparatus of claim 1, further comprising: the tablet, the tabletformulated to include sufentanil.
 11. An apparatus, comprising: adelivery tip defining a curved delivery passage, a distal end portion ofthe delivery tip defining an exit port; a push rod, at least a portionof the push rod being movably disposed in the delivery passage, a distalend portion of the push rod being within the delivery passage when thepush rod is in a first position, the distal end portion of the push rodconfigured to deliver a drug-containing tablet through the exit portwhen the push rod is moved from its first position to a second position;a shroud coupled to the distal end portion of the delivery tip, theshroud at least partially disposed about and spaced apart from the exitport such that the shroud inhibits contact by at least one of a tongueor a sublingual membrane with the exit port when the distal end portionof the delivery tip is disposed within a mouth, at least a portion ofthe shroud being constructed from a hydrophilic material; and a sealdisposed about the exit port, a portion of the seal defining a slitconfigured to permit passage of the tablet and the distal end portion ofthe push rod therethrough during delivery of the tablet, the portion ofthe seal configured to maintain sealing contact with at least one of thetablet or the push rod when the push rod is moved from its firstposition to its second position to deliver the tablet.
 12. The apparatusof claim 11, wherein the push rod is flexible.
 13. The apparatus ofclaim 11, wherein the distal end portion of the push rod defines anopening therethrough, the apparatus further comprising: a sensorconfigured to detect the passing of the opening when the push rod ismoved within the delivery passage.
 14. The apparatus of claim 11,wherein the distal end portion of the push rod defines an openingtherethrough, the apparatus further comprising: an optical sensorassembly having a first portion and a second portion, the optical sensorassembly configured to detect the passing of the opening when the pushrod is moved within the delivery passage between the first portion andthe second portion.
 15. The apparatus of claim 11, further comprising: asensor assembly configured to detect a position of the push rod when thepush rod is moved within the delivery passage.
 16. The apparatus ofclaim 11, further comprising: a sensor configured to distinguish thepassing of a shipping tablet within the delivery passage from thedrug-containing tablet within the delivery passage.
 17. The apparatus ofclaim 11, wherein the seal is configured to maintain contact with atleast one of the tablet or the push rod when the push rod is moved fromits first position to its second position to deliver the tablet.
 18. Anapparatus, comprising: a delivery tip defining a curved deliverypassage, a distal end portion of the delivery tip defining an exit port;a push rod, at least a portion of the push rod being movably disposed inthe delivery passage, a distal end portion of the push rod being withinthe delivery passage when the push rod is in a first position, thedistal end portion of the push rod configured to deliver adrug-containing tablet through the exit port when the push rod is movedfrom its first position to a second position, the distal end portion ofthe push rod including a sensor portion configured to allow light topass therethrough to allow detection of a position of the push rodwithin the delivery passage; a shroud coupled to the distal end portionof the delivery tip the shroud at least partially disposed about andspaced apart from the exit port such that the shroud inhibits contact byat least one of a tongue or a sublingual membrane with the exit portwhen the distal end portion of the delivery tip is disposed within amouth, at least a portion of the shroud being constructed from ahydrophilic material; and a seal disposed about the exit port, a portionof the seal defining a slit configured to permit passage of the tabletand the distal end portion of the push rod therethrough during deliveryof the tablet, the portion of the seal configured to maintain sealingcontact with at least one of the tablet or the push rod when the pushrod is moved from its first position to its second position to deliverthe tablet.
 19. The apparatus of claim 18, wherein the sensor portion ofthe push rod defines an opening therethrough, the apparatus furthercomprising: a sensor configured to detect the passing of the openingwhen the push rod is moved within the delivery passage.
 20. Theapparatus of claim 18, wherein the sensor portion of the push roddefines an opening therethrough, the apparatus further comprising: anoptical sensor assembly having a first portion and a second portion, theoptical sensor assembly configured to detect the passing of the openingwhen the push rod is moved within the delivery passage between the firstportion and the second portion.
 21. The apparatus of claim 18, furthercomprising: a sensor configured to distinguish the passing of a shippingtablet within the delivery passage from the drug-containing tabletwithin the delivery passage.